Disease of the Month

Nephronophthisis-Associated Ciliopathies

Friedhelm Hildebrandt and Weibin Zhou
JASN June 2007, 18 (6) 1855-1871; DOI: https://doi.org/10.1681/ASN.2006121344

Abstract

Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, represents the most frequent genetic cause of end-stage kidney disease in the first three decades of life. Contrary to polycystic kidney disease, NPHP shows normal or diminished kidney size, cysts are concentrated at the corticomedullary junction, and tubulointerstitial fibrosis is dominant. NPHP can be associated with retinitis pigmentosa (Senior-Løken syndrome), liver fibrosis, and cerebellar vermis aplasia (Joubert syndrome) in approximately 10% of patients. Positional cloning of six novel genes (NPHP1 through 6) as mutated in NPHP and functional characterization of their encoded proteins have contributed to the concept of “ciliopathies.” It has helped advance a new unifying theory of cystic kidney diseases. This theory states that the products of all genes that are mutated in cystic kidney diseases in humans, mice, or zebrafish are expressed in primary cilia or centrosomes of renal epithelial cells. Primary cilia are sensory organelles that connect mechanosensory, visual, osmotic, and other stimuli to mechanisms of cell-cycle control and epithelial cell polarity. The ciliary theory explains the multiple organ involvement in NPHP regarding retinitis pigmentosa, liver fibrosis, ataxia, situs inversus, and mental retardation. Mutations in NPHP genes cause defects in signaling mechanisms, including the noncanonical Wnt signaling pathway. The “ciliopathy” NPHP thereby is caused by defects in tissue differentiation and maintenance as a result of impaired processing of extracellular cues. Nephrocystins, the proteins that are encoded by NPHP genes, are highly conserved in evolution. Positional cloning of additional causative genes of NPHP will elucidate further signaling mechanisms that are involved, thereby establishing therapeutic approaches using animal models in mouse, zebrafish, and Caenorhabditis elegans.

Nephronophthisis: A Frequent Genetic Cause of Kidney Failure in Children

Renal Involvement

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that constitutes the most frequent genetic cause for end-stage kidney disease (ESKD) in the first three decades of life (1–4). Three clinical forms of NPHP have been distinguished by onset of ESKD: Infantile (5), juvenile (6), and adolescent NPHP (7), which manifest with ESKD at the median ages of 1, 13, and 19 yr, respectively. Initial symptoms are relatively mild (except in infantile NPHP type 2) and consist of polyuria, polydipsia with regular fluid intake at nighttime, secondary enuresis, and anemia (8). At an average age of 9 yr, a slightly raised serum creatinine is noted, before ESKD invariably develops within a few years. Renal ultrasound reveals increased echogenicity. Later, cysts appear at the corticomedullary junction within kidneys of normal or slightly reduced size (Figure 1, A and B) (9). Renal histology reveals a characteristic triad of tubular basement membrane disruption, tubulointerstitial nephropathy, and corticomedullary cysts (Figure 1C) (10,11). In NPHP, cysts arise from the corticomedullary junction of the kidneys (Figure 1, A and B). Because kidneys size is normal or slightly reduced (except in infantile NPHP type 2, in which there is moderate renal enlargement), cysts seem to develop e vacuo by loss of normal tissue. This is in contrast to polycystic kidney disease (PKD), in which cysts are evenly spread out over the entire organ and lead to gross enlargement of the kidneys (4).

Figure 1.
Figure 1.

Morphology of nephronophthisis (NPHP). (A) Macroscopic pathology reveals cysts that arise from the corticomedullary junction of normal-sized kidneys. (B) Renal ultrasound demonstrates increased echogenicity, loss of corticomedullary differentiation, and the presence of cysts. In contrast to polycystic kidney disease (PKD), in NPHP, cysts are concentrated at the corticomedullary border and kidneys are not enlarged. (C) Renal histology in NPHP shows the characteristic triad of renal tubular (and glomerular) cysts, tubular membrane disruption, and tubulointerstitial cell infiltrates with interstitial fibrosis and periglomerular fibrosis. Adapted from Hildebrandt et al. (9a); and courtesy of D. Bockenhauer.

NPHP is inherited in an autosomal recessive mode. This includes NPHP variants with extrarenal manifestations (4). NPHP has previously been grouped together with the clinical entity of medullary cystic kidney disease (MCKD) (6,10) because of similarities of clinical and pathologic features (12). Both NPHP and MCKD feature corticomedullary cysts in kidneys of normal or slightly reduced size. However, MCKD is clearly distinct from NPHP regarding multiple aspects: (1) MCKD follows autosomal dominant inheritance, (2) ESKD occurs in the fourth decade and later, and (3) in MCKD there is no extrarenal involvement other than hyperuricemia and gout.

NPHP was first described by Smith and Graham in 1945 (2) and by Fanconi et al. (3), who introduced the term “familial juvenile nephronophthisis.” Since then, >300 cases have been published in the literature (10). In NPHP, the earliest presenting symptoms are polyuria, polydipsia, decreased urinary concentrating ability, and secondary enuresis. They occur in >80% of cases (13) and start at approximately 6 yr of age. Anemia and growth retardation develop later in the course of the disease (8). Regular fluid intake at nighttime is a characteristic feature of the patient’s history and starts at approximately age 6 yr. Because of the mild nature of symptoms and the lack of edema, hypertension, or urinary tract infections, there is often a delay in the diagnosis of NPHP. This causes a risk for sudden death from fluid and electrolyte imbalance. Disease recurrence has never been reported in kidneys that were transplanted to patients with NPHP (14). By positional cloning, we and others have identified recessive mutations in six different novel genes as causing NPHP: NPHP1 (15,16), NPHP2/inversin (17), NPHP3 (18), NPHP4 (19), NPHP5 (20), and NPHP6 (21), defining NPHP types 1, 2, 3, 4, 5, and 6, respectively. This has made definite molecular genetic diagnostics possible (www.renalgenes.org). Homozygous deletions in the NPHP1 gene account for approximately 25% of all NPHP cases, whereas the other genes contribute <2% each. As expected in a recessive disease, penetrance of the renal phenotype seems to be 100%.

In NPHP, chronic renal failure develops within the first three decades of life (7,22,23). Infantile NPHP, which is characterized by mutations in NPHP2/inversin, leads to ESKD between birth and age 3 yr (17,23). In a study conducted in 46 children who had juvenile NPHP type 1 caused by mutations in the NPHP1 gene, a serum creatinine of 6 mg/dl was reached at a median age of 13 yr (range 4 to 20 yr) (6,22). Similarly, the median age of ESKD in patients with mutations in the NPHP5 gene was 13 yr (20). The median time lapse between a serum creatinine of 2 and 4 mg/dl was 32 mo and between 4 and 6 mg/dl was 10 mo (24). In patients with adolescent NPHP as a result of mutations in the NPHP3 gene, ESKD develops by 19 yr of age (18). If renal failure has not developed by the age of 25 yr, then the diagnosis of recessive NPHP should be questioned and autosomal dominant MCKD considered as a differential diagnosis. In MCKD, which follows autosomal dominant inheritance, ESKD occurs later in life. MCKD types 1 and 2 show a median onset of ESKD at 62 (25) and 32 yr (26), respectively. MCKD type 2 can be positively diagnosed by detection of mutations in the UMOD gene that encodes uromodulin/Tamm-Horsfall protein.

Epidemiology

NPHP has been reported from virtually all regions of the world (13). The incidence of the disease has been given as nine patients per 8.3 million (27) in the United States or one in 50,000 live births in Canada (10,28). Although a rare disorder, it represents the most frequent genetic cause of ESKD in the first three decades of life and is a major cause of ESKD in children, accounting for 10 to 25% of these patients in Europe (13,29–31). In the North American pediatric ESKD population, pooled data indicate a prevalence of approximately 5% of all children with ESKD (32,33).

Extrarenal Manifestations of Eye, Brain, and Liver

NPHP may be associated with tapetoretinal degeneration (Senior-Løken syndrome [SLSN] [34,35]), cerebellar vermis aplasia (Joubert syndrome [JBTS] [36,37]), ocular motor apraxia type Cogan (38), mental retardation (21,39), liver fibrosis (40), or cone-shaped epiphyses of the phalanges (Mainzer-Saldino syndrome [41]). Infantile NPHP type 2 (17) can be associated with situs inversus (17), retinitis pigmentosa (42), or cardiac ventricular septal defect (17). The ciliary theory of NPHP elucidates the pathogenic basis of extrarenal organ involvement regarding retinitis pigmentosa, liver fibrosis, ataxia, situs inversus, and mental retardation.

Retinal Involvement (SLSN)

SLSN, represented by the concomitant occurrence of NPHP with retinitis pigmentosa, was first described by Contreras (43), Senior (34), and Løken (35). Three different terms have been used in the literature to describe the retinal findings of SLSN: Retinitis pigmentosa, tapetoretinal degeneration, and retinal-renal dysplasia. This most likely reflects a spectrum within the pathogenesis that includes developmental defects (dysplasia) as well as defects of tissue maintenance (degeneration) (44). In children with recessive mutations in the NPHP1, 2, 3, and 4 genes, retinitis pigmentosa occurs in approximately 10% of all affected families, without any obvious genotype/phenotype correlation. Whether patients with retinal involvement carry an additional mutation in an unknown modifier gene is an open question. Early-onset and late-onset types of SLSN have been distinguished. The early-onset type seems to represent a form of Leber’s congenital amaurosis, because children exhibit coarse nystagmus and/or blindness at birth or develop these symptoms within the first 2 yr of life (45). It is interesting that patients with mutations in the NPHP5 or NPHP6 genes exhibit early-onset retinitis pigmentosa in all known cases (20,21). Fundoscopic alterations are present in all patients with late-onset SLSN by the age of 10 yr. The late-onset form manifests first with night blindness, followed by development of blindness during school age. Retinal degeneration is characterized by a constant and complete extinction of the electroretinogram, which precedes the development of visual and fundoscopic signs of retinitis pigmentosa (46). The kidney involvement in SLSN is identical clinically to what is known from patients with NPHP without ocular involvement regarding age of onset, symptoms, and histology of renal disease.

Cerebellar Vermis Aplasia (JBTS)

In JBTS, a developmental disorder with multiple organ involvement, NPHP or cystic dysplasia occurs in association with coloboma of the eye (or retinal degeneration); with aplasia/hypoplasia of the cerebellar vermis causing ataxia; and with the facultative symptoms of psychomotor retardation, polydactyly, occipital encephalocele, and episodic neonatal tachypnea/dyspnea (36,37,47–49). A pathognomonic diagnostic feature of JBTS on axial magnetic resonance imaging of the brain is the presence of prominent superior cerebellar peduncles, termed the “molar tooth sign” of the midbrain-hindbrain junction (49,50). In patients with the association of JBTS and NPHP, mutations have been described in three different genes, NPHP1 (37,49,50), AHI (51,52) (JBTS type 3), and NPHP6 (21,53). Patients with JBTS have abnormal axonal decussation (crossing in the brain) that affects the corticospinal tract and superior cerebellar peduncles, thereby explaining the motor and behavioral abnormalities (54). Some patients also have abnormal cerebral structure with cortical polymicrogyria (55). Ocular motor apraxia type Cogan, defined as the transient inability of horizontal eye movements in the first few years of life, may be associated with JBTS. This symptom has been described in patients with mutations in the NPHP1 (38,56) (“JBTS4”) and NPHP4 (57) genes. It may be due to defects in the nuclei of the abducens nerve, which contain both ipsilaterally projecting motor neurons and contralaterally projecting interneurons, or supranuclear control regions such as the pontine paramedian reticular formation that projects to the abducens and oculomotor nuclei, which has been postulated for other forms of horizontal gaze palsy (58). Defects in axon guidance may be related to defects in renal tubule development by shared signaling pathways (see Signal Mechanisms Relevant for NPHP). Two additional loci for JBTS have been identified: JBTS1 on chromosome 9q34.3 (59) and JBTS2/CORS2 on chromosome 11p12-q13.3 (60).

Liver Fibrosis and Skeletal Changes

NPHP may be associated with liver fibrosis (40,61–63). Patients develop hepatomegaly and moderate portal fibrosis with mild bile duct proliferation. This pattern differs from that of classical congenital hepatic fibrosis, whereby biliary dysgenesis is prominent. A recessive mutation in the NPHP3 gene was recently described in a patient with NPHP and liver fibrosis (18). Hepatic involvement in NPHP type 2 (infantile NPHP) seems to involve only transient elevation of transaminases (23). The association of NPHP with cone-shaped epiphyses of the phalanges (type 28 and 28A), known as Mainzer-Saldino syndrome, was first published by Mainzer et al. (41) in patients who also had retinal degeneration and cerebellar ataxia.

Situs Inversus

The presence of situs inversus was shown in a patient with infantile NPHP and mutations in the NPHP2/inversin gene (17). Therefore, the role of inversin in left–right axis specification that had been described in mice was confirmed in humans (64,65). The patient with situs inversus also had a cardiac ventricular septal defect as a heterotaxy phenotype. This finding was analogous to the randomization of heart looping that was seen in nphp2/inversin knockdown experiments in zebrafish. Recently, it has become apparent that products of other genes that are associated with renal cystic disease (in addition to inversin) are important for left–right axis determination of the body plan (66,67). The gene PKD2, mutations in which cause autosomal dominant PKD and that encodes the calcium release channel polycystin-2, had been shown in a Pkd2−/− mouse model to represent a gene that regulates left–right axis determination, acting upstream of Nodal, Ebaf, Leftb, and Pitx2 (68,69).

Other Syndromes with NPHP

Bardet-Biedl syndrome (BBS) exhibits renal histology that is similar to NPHP (70,71). Positional cloning of recessive genes that are mutated in BBS has revealed that the molecular relation between NPHP and BBS may lie in coexpression of the respective gene products in primary cilia, basal bodies, and centrosomes of renal epithelial cells (72). For BBS, an oligogenic inheritance pattern has been described. This refers to the finding that mutations in more than one BBS gene may be required for full penetrance of some aspects of organ involvement (73).

Further disease variants have been described in association with NPHP, including Jeune syndrome (asphyxiating thoracic dysplasia) (74–77), Ellis van Creveld syndrome (78), RHYNS syndrome (retinitis pigmentosa, hypopituitarism, NPHP, and skeletal dysplasia) (79), Alstrom syndrome (retinitis pigmentosa, deafness, obesity, and diabetes without mental defect, polydactyly, or hypogonadism) (80), and Meckel-Gruber syndrome (81,82), which in the case of MKS3 mutations can be allelic with JBTS (83). In Alstrom syndrome, the single underlying gene, ALMS1, encodes a novel protein that contains coiled-coil domains and a putative nuclear localization signal, as well as serine-rich and histidine-rich regions (84,85). ALMS1 forms a part of the centrosome (86,87). This, together with the finding that BBS proteins localize to centrosomes, confirms the role of centrosomal proteins in cystic kidney diseases that are associated with diabetes, obesity, and retinitis pigmentosa (88,89). Additional NPHP-associated disorders are Sensenbrenner syndrome (cranioectodermal dysplasia) (90,91) and Arima syndrome (cerebro-oculo-hepato-renal syndrome) (92–94). NPHP has also been described in association with ulcerative colitis (95).

Positional Cloning Reveals Seven Causative Genes for NPHP

Since its first description in 1945 (2,3), the pathogenesis of NPHP had been elusive. Positional cloning revealed novel genes that cause NPHP when mutated. These are monogenic recessive genes, suggesting that mutations in each single one of these genes is sufficient to cause NPHP in a patient who bears these mutations, indicating that their products are necessary for normal kidney function. Positional cloning thereby generated new insights into disease mechanisms of NPHP and demonstrated that they are related to signaling mechanisms of sensory cilia, centrosomes, and planar cell polarity (1,72,96). Seven NPHP-associated genes have been identified so far: NPHP1 through 6 and AHI1 (15–21,54,55,57) (Table 1).

View this table:
Table 1.

Genetics and frequency of extrarenal associations in NPHP

NPHP1

We identified mutations in NPHP1 as causing juvenile NPHP type 1 (15,16). NPHP1 encodes nephrocystin-1, a protein that interacts with components of cell–cell and cell–matrix signaling, including p130Cas (97), focal adhesion kinase 2 (98), tensin, and filamin A and B (99,100). It also interacts with the products of other NPHP genes, such as nephrocystin-2/inversin (17), nephrocystin-3 (18), and nephrocystin-4 (57,101). Nephrocystin-1 localizes to adherens junctions and focal adhesions of renal epithelial cells (99,100), which are involved in cell–cell and cell–basement membrane communications, respectively (101,102) (Figure 2).

Figure 2.
Figure 2.

Cystoproteins are proteins of genes that are mutated in cystic kidney diseases of humans, mice, or zebrafish. They share the common feature of expression in primary cilia, basal bodies, or centrosomes. Depending on cell-cycle stage, some cystoproteins localize to adherens junctions or focal adhesions. Many cystoproteins have been localized to more than one intracellular domain. The speckled arrow in the primary cilium indicates the direction of anterograde transport along the microtubule system mediated by kinesin 2, a heterotrimeric protein that is composed of two motor units (Kif3a and Kif3b) and one nonmotor unit (KAP3). AJ, adherens junction; BB, basal body; Cen, centriole; ER, endoplasmic reticulum; FAP, focal adhesion plaque; TJ, tight junction; PC-1, polycystin-1; PC-2, polycystin-2. Modified from Watnick and Germino (72), with permission.

NPHP2

The renal cystic changes of infantile NPHP (NPHP type 2) combine clinical features of NPHP and of PKD (5). Guided by mapping of a locus for infantile NPHP to chromosome 9q21-q22 (23) and by the observation that a deletion in the inversin (Invs) gene causes renal cystic phenotype in the inv/inv mouse model (64,65), we identified mutations in human inversin (INVS) as the cause of infantile NPHP (type 2) with and without situs inversus (17). Inversin interacts with nephrocystin-1 and with β-tubulin, which constitutes the microtubule axoneme of primary cilia. We demonstrated that nephrocystin-1 and inversin localize to primary cilia of renal tubular cells (17)—the same subcellular compartment that was identified as central to the pathogenesis of PKD (1,66,103). This was one of the first findings to support a unifying theory of renal cystogenesis (1,72), which states that proteins that, when mutated, cause renal cystic disease in humans, mice, or zebrafish (“cystoproteins”) are expressed in primary cilia, basal bodies, or centrosomes (66,72). The interaction and co-localization to cilia of nephrocystin-1, inversin, and β-tubulin provided a functional link between the pathogenesis of NPHP, the pathogenesis of PKD, primary cilia function, and left–right axis determination (17). The functional relationship between ciliary expression of these so-called “cystoproteins” (proteins mutated in cystic kidney disease) and the renal cystic phenotype, however, is still somewhat unclear. One of the first concepts for this relationship proposes that cilia may act as mechanosensors to sense fluid movement in the kidney tubule, where polycystin-1 transmits the signal to polycystin-2, which is a TRP type calcium channel. This would produce sufficient Ca2+ influx to induce Ca2+ release from intracellular storage, which then regulates numerous intracellular signaling activities that are linked to the regulation of cell cycle and planar cell polarity (103). In particular, inversin/NPHP2 function has been implicated in signaling mechanisms of planar cell polarity (see The Wnt Pathway) (104). Okada et al. (105) previously demonstrated that inversin is needed to position the cilia in cells of the ventral node.

NPHP3

By positional cloning in a large Venezuelan kindred (7), we identified mutations in NPHP3 as responsible for adolescent NPHP (18). We demonstrated that mutations in the murine ortholog Nphp3 cause the renal cystic mouse mutant pcy (18), which was recently shown to be responsive to treatment with a vasopressin receptor antagonist (106).

NPHP4

Mutations in NPHP4 were identified by homozygosity mapping and total genome search for linkage (19,57,107). The encoded protein, nephrocystin-4/nephroretinin, is in a complex with other proteins that are involved in cell adhesion and actin cytoskeleton organization, such as nephrocystin-1, p130Cas, Pyk2, tensin, filamin, and α-tubulin. In polarized epithelial cells, nephrocystin-4 localizes to primary cilia, basal bodies, and the cortical actin cytoskeleton, whereas in dividing cells, it localizes to centrosomes (101). Nephrocystin-4 is conserved in Caenorhabditis elegans and expressed in ciliated head and tail neurons of the nematode (108). Upon knockdown, it exhibits a male mating phenotype, similar to orthologs of other genes that are mutated in cystic kidney disease (108).

NPHP5

Recently, we identified another novel gene (NPHP5) as being mutated in NPHP type 5 (20). It is interesting that all mutations found were truncations of the encoded protein nephrocystin-5, and all patients had early-onset retinitis pigmentosa (SLSN). Nephrocystin-5 contains two IQ domains, which directly interact with calmodulin (20) and is in a complex with the retinitis pigmentosa GTPase regulator, which when defective causes X-linked retinitis pigmentosa. Both nephrocystin-5 and retinitis pigmentosa GTPase regulator localize to connecting cilia of photoreceptors and in primary cilia of renal epithelial cells (20). The fact that connecting cilia of photoreceptors are the structural equivalents of primary cilia of renal epithelial cells may explain retinal involvement in the retinal-renal syndrome SLSN.

NPHP6

Very recently, we identified by positional cloning of recessive truncating mutations in a novel gene NPHP6/CEP290, which encodes a centrosomal protein, as the cause of NPHP type 6 and JBTS type 5 (21). We demonstrated that abrogation of NPHP6 function in zebrafish causes planar cell polarity (convergent extension) defects and recapitulates the human phenotype of NPHP type 6, including renal cysts, retinitis pigmentosa, and cerebellar defects (21). In addition, a defect in cell size control and morphogenesis was found upon nphp6 knockdown in the nonvertebrate Ciona intestinalis. Nephrocystin-6 modulates the activity of ATF4/CREB2, a transcription factor that is implicated in cAMP-dependent renal cyst formation (106). Nephrocystin-6 is expressed in centrosomes and the mitotic spindle in a cell cycle–dependent manner. Its identification establishes a link between centrosome function and tissue architecture in the pathogenesis of cystic kidney disease, retinitis pigmentosa, and central nervous system development. Mutations in NPHP6/CEP290 have been confirmed as causing JBTS with and without renal involvement (21,53). It is interesting that a 300–amino acid in-frame deletion of NPHP6/CEP290 caused retinal degeneration only, without renal or cerebellar involvement in the rds16 mouse model (109). This is in accordance with the recent finding that a hypomorphic mutation of NPHP6/CEP290 represents the most frequent cause of Leber’s congenital amaurosis (110).

AHI1

Finally, mutations in AHI1 have been detected in patients with JBTS with and without renal involvement (51,52,54,55). Taken together, these findings indicate that the nephrocystin proteins are involved in functions of sensory cilia, cell polarity, and cell division (101).

Cilia: A Unifying Theory for Cystic Kidney Disease

The demonstration that nephrocystin-1 and inversin/NPHP-2 localize to primary cilia of renal tubular cells (17) was among the first findings to support a new unifying theory of renal cystogenesis (72). This theory states that proteins that, when mutated, cause renal cystic disease in humans, mice, or zebrafish (“cystoproteins”) are expressed in primary cilia, basal bodies, or centrosomes (66,72) (Figure 3).

Figure 3.
Figure 3.

Cilia structure and intraflagellar transport (IFT). (A) A typical cilium consists of an axoneme of nine doublet microtubules. Each doublet arises from the inner two microtubules of the basal body microtubule triplets. The axoneme is surrounded by a specialized ciliary membrane that is separated from the cell membrane by a zone of transition fibers. (B) A cross-section of 9 + 2 and 9 + 0 cilium. Cilia are broadly divided into two types on the basis of the presence or absence of a central pair of microtubule singlets in the axoneme (9 + 2 or 9 + 0 structure, respectively). Inner and outer dynein arms, which are usually associated with 9 + 2 cilia, can be present in either type of cilium and are important for ciliary motility. Ciliary assembly and maintenance is accomplished by IFT, which relies on the microtubule motor proteins kinesin 2 and cytoplasmic dynein to transport IFT protein complexes and their associated cargo up and down the length of the cilium (depicted in A). Eb1, end-binding protein 1. Adapted from Bisgrove and Yost (110a).

Cilia Structure and Function

The cilium is a hair-like structure that extends from the cell surface into the extracellular space. Virtually all vertebrate cell types have cilia in developing or mature tissue. Cilia consist of a microtubule-based axoneme covered by a specialized plasma membrane. The axoneme has nine peripheral microtubule doublets arranged around a central core. There may be two central microtubules (9 + 2 or 9 + 0 axoneme; Figure 3). 9 + 2 cilia usually have dynein arms that link the microtubule doublets and are motile, whereas most 9 + 0 cilia lack dynein arms and are nonmotile (“primary cilia”). The ciliary axoneme is anchored in the basal body, a microtubule-organizing center derived from the older of the two centrioles. The transition zone at the junction of the basal body acts as a filter for the molecules that can pass into or out of the cilium. Nephrocystin-1 is localized at the transition zone of epithelial cells (111). During generation of cilia (ciliogenesis), cilia elongate from the basal body by the addition of new axonemal subunits to the distal tip, the plus end of the microtubules. Axonemal and membrane components are transported in raft macromolecular particles (complex A and B) by so-called intraflagellar transport (IFT) along the axonemal doublet microtubules (Figure 3) (112). Anterograde transport toward the tip is driven by heterotrimeric kinesin 2, which contains motor subunits Kif3a and Kif3b and a nonmotor subunit. Mutations of Kif3a cause renal cysts in mice (113). Kinesins also help form signaling complexes within the ciliary membrane. Retrograde transport back to the cell body occurs via the motor protein cytoplasmic dynein 1B (114).

The unexpected convergence in primary cilia of proteins that underlie cystic kidney diseases is supported by the following findings: (1) there is high evolutionary conservation of the proteins involved (Figure 4, A through D), (2) most of these proteins interact with each other (Figure 4C), and (3) clinical phenotypes are related to tissue-specific expression in the sensory cilia (Figure 4, E through G).

Figure 4.
Figure 4.

The cilia/basal body hypothesis of renal cystic disease and related disorders. This illustration summarizes the new unifying pathogenic theory of cystic kidney disease, which states that virtually all proteins that are mutated in cystic kidney disease of humans, mice, or zebrafish (“cystoproteins”) show expression of their encoded proteins in primary cilia, basal bodies, or centrosomes. The horizontal axis symbolizes the flow of genetic information from genes over proteins to disease phenotypes. The vertical axis represents evolutionary time. (A) On the evolutionary scale, genes that are responsible for renal cystic disease in vertebrates are shown, including the unicellular organism Chlamydomonas reinhardtii. (B) Many of the orthologs of human cystic kidney disease genes are expressed in ciliated neurons of head and tail of the nematode Caenorhabditis elegans, where they lead to a male mating phenotype when knocked down (e.g., lov-1 or nph-4) (see E). Most proteins that are mutated in Bardet-Biedl syndrome (BBS) are conserved as basal body components of motile cilia (flagella) C. reinhardtii, where mutations in these genes lead to a phenotype of defective IFT or propulsion (see E). (C) Many cystoproteins directly interact with each other (e.g., NPHP1 and NPHP2/inversin). (D) Recently, it was discovered that the products of all genes that are mutated in cystic kidney diseases of humans, mice, or zebrafish show expression of their encoded proteins in primary cilia, basal bodies, or centrosomes. These findings placed primary cilia and centrosomes at the center of these disease processes (D has no vertical dimension). (E through G) The convergence of the pathogenesis at sensory cilia that serve distinct functions in different tissues may explain the broad organ involvement (pleiotropy) of NPHP and BBS that includes many different organ systems through defects of sensory cilia. Pleiotropic phenotypes in NPHP or BBS include cystic kidney disease, retinitis pigmentosa, infertility, diabetes, and other diseases of premature aging of organs.

Cilia: Conserved Modules to Sense Cell External Signals

It is becoming apparent that primary cilia are highly conserved structures for sensing of a wide variety of extracellular cues by a broad variety of specialized tissues. A common “theme” conserved through evolution seems to suggest that many times when cells are to receive cues from the outside of the cell, they use a primary cilium. A broad range of cues can be received by specific ciliary receptors. These include photosensation (rhodopsin), mechanosensation (polycystin-1 and -2), osmosensation, and olfactory sensation (seven-membrane spanning olfactory receptors). The decision rules by which cells place a specific receptor molecule into the cilium are unknown. In general, it seems that the pathogenesis of ciliopathies is based on an inability of epithelial cells to sense or process extracellular cues (115).

Evolutionary Conservation of Cystoproteins

For many “cystoproteins,” the renal cystic phenotype is conserved among vertebrates. For example, mutations in inversin lead to NPHP type 2 in humans, mice, and zebrafish (Figure 4) (17). At least two nephrocystins are conserved even in the nematode C. elegans by amino acid sequence, functional features, and their expression patterns and knockdown phenotypes: Nphp-1 and nphp-4 are expressed in head (amphid) and tail (phasmid) neurons, which are ciliated osmosensor neurons of C. elegans (Figure 4A) (108,116). Localization of nephrocystin-1 and -4 to some of these ciliated neurons overlaps with localization of the cystoprotein orthologs polycystin-1 (lov-1) and polycystin-2 (pkd-2) and with many orthologs of BBS proteins (117). Knockdown of nphp-1 and nphp-4 leads to impaired male mating behavior (108), similar to what has been described for lov-1 and pkd-2 mutants (118). These data have been confirmed and refined for specific neuronal cell type (119,120). In addition, a role for nphp-4 in the lifespan of the worm has been demonstrated (121). In C. elegans, bbs-7 and bbs-8 are required for the correct localization/motility of the IFT proteins osm-5/polaris and che-11 (122). A bioinformatics approach based on the ciliary/basal body hypothesis of BBS pathogenesis also helped to identify the cystoprotein BBS5 (123). Using bioinformatic screens for ciliary genes in combination with data from positional cloning, mutations in ARL6 were identified as being responsible for BBS type 3 (124,125). ARL6, a small GTPase, is specifically expressed in ciliated cells and undergoes IFT.

Evolutionary conservation of cystoproteins goes even further: Some cystoproteins have been conserved over >1.5 billion years of evolution from the unicellular organism Chlamydomonas reinhardtii to vertebrates (Figure 4, A and B). C. reinhardtii uses two motor cilia (flagella) for locomotion. Strikingly, nephrocystin-4 and at least six proteins that are mutated in BBS are conserved in C. reinhardtii where they are part of the basal body proteome (117,126). Defects of cystoprotein orthologs in C. reinhardtii have deficient IFT and flagellar propulsion (127).

Nephrocystin Complexes

Many cystoproteins participate in protein–protein interaction complexes (Figure 4C). These interactions may partially explain why mutations in different NPHP genes lead to similar phenotypes. Some of the domains that occur in cystoproteins are shared between different proteins. Coiled-coil domains, for example, occur in six of eight proteins that are defective in NPHP-like diseases (nephrocystin-1, -2, -3, -5, and -6 and ALMS1). Nephrocystin-1 is targeted to the transition zone of motile and primary cilia (111), and casein kinase 2–mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates phosphofurin acidic cluster sorting protein (PACS)-1 binding and is essential for co-localization of nephrocystin with PACS-1 at the base of cilia (128). The basal body/centrosomal expression of proteins that are involved in NPHP has led to identification of mutations in NPHP6/CEP290 as the cause of NPHP type 6 (JBTS type 5). Its gene product nephrocystin-6/Cep290 (21) is part of the centrosomal proteome (86).

Extrarenal Organ Involvement by Ciliary Dysfunction

A prominent feature of NPHP is that in a certain percentage of cases, there can be involvement of multiple organs (pleiotropy) other than the kidney. In some instances, there seems to be a genotype/phenotype correlation regarding pleiotropy. For instance, there is involvement of the retina in all known cases with mutations of NPHP5 or NPHP6. In other instances, such as NPHP1 mutations, the molecular basis of eye involvement is unknown. The pleiotropy of NPHP has now found a potential explanation in the ciliary hypothesis of cystic kidney diseases (Figure 4, E through G). The extrarenal organ involvement in NPHP by organ system is discussed as follows.

Retinal Degeneration.

The renal-retinal involvement in SLSN can be explained by the fact that the primary cilium of renal epithelial cells is a structural equivalent of the connecting cilium of photoreceptor cells in the retina. We have shown that nephrocystin-5 and nephrocystin-6 are expressed in the connecting cilia of photoreceptors (20,21). In analogy to motor transport along the axoneme of primary cilia in kidney epithelial cells, in the connecting cilia of photoreceptors, cargo is trafficked along microtubule tracks from the photoreceptor inner segment to the outer segment via a motor protein complex that contains kinesin 2 and back to the cell body via a cytoplasmic dynein (Figure 5) (129). In this way, 10 billion molecules of the visual pigment rhodopsin are trafficked up and down the connecting cilia per human retina per day.

Figure 5.
Figure 5.

Primary (nonmotile) cilia of renal epithelial cells and connecting cilia of retinal photoreceptors are analogous structures. In the primary cilium (A) of renal epithelial cells (B), “cargo” proteins are trafficked along the microtubule tracks from the region of the Golgi stack to the tip of the cilia via the motorprotein kinesin 2 and back down via cytoplasmic dynein 1b. (C) In an analogous manner, approximately 109 molecules of the visual pigment rhodopsin are transferred up and down the connecting cilia per human retina per day. Adapted from references (66,129).

Liver Fibrosis.

Both NPHP and BBS can be associated with liver fibrosis (40), whereas autosomal recessive PKD is associated with bile duct ectasia. Bile duct involvement in these cystic kidney diseases may be explained by the ciliary theory, because the epithelial cells lining bile ducts (cholangiocytes) possess primary cilia (Figure 4, F and G).

Central Nervous System.

Recent findings suggest that oculomotor apraxia type Cogan (associated with NPHP1 and NPHP4 mutations), cerebellar vermis hypoplasia (in JBTS), and mental retardation (in NPHP type 6) may be due to defects in microtubule-associated functions during neurite outgrowth and axonal guidance. Mechanotransport along microtubules plays a role not only in intraciliary but also in axonal transport (130). An example is the motor protein KIF3A, which is mutated in a renal cystic mouse model and also plays a role in axonal transport (113). Because the malformations of the cerebellum that occur in JBTS (37) consist of abnormal “wiring” of decussating (crossing) neurons, impaired axonal outgrowth and axon guidance may be central to the neurologic defects in JBTS, in analogy to the lissencephaly phenotype that is caused by the centrosomal proteins LIS1 and doublecortin (131).

Congenital Cardiac Malformations.

In a patient with infantile NPHP, we observed a ventricular septal defect as a congenital cardiac malformation (17). This developmental defect may be viewed as a “heterotaxy” (left–right orientation) phenotype that is caused by the same mechanism (68) that leads to situs inversus in this patient. The phenotypic combination of NPHP, situs inversus, and cardiac septal defect on the basis of inversin mutations is observed in humans, mice, and zebrafish (17).

Obesity.

Obesity is part of the clinical spectrum of the ciliopathy BBS, and excessive obesity has been described in children with NPHP6 mutations after renal transplantation (B. Hoppe, University of Cologne, Germany, personal communication, 2006). It is interesting that in the Bbs6 knockout mouse model, obesity was associated with hyperphagia and decreased activity of the mice (132).

Signaling Mechanisms Relevant for NPHP

Nephrocystins and other cystoproteins are expressed in different subcellular compartments in a cell cycle–dependent manner (21,133). These subcellular compartments include focal adhesions, adherens junctions, cilia, basal bodies, centrosomes, and the mitotic spindle (Figure 6). It is still mostly unclear which of these subcellular localizations are most proximal to the pathogenesis of NPHP or other cystic kidney diseases. In relation to these subcellular localizations, many hypotheses on mechanisms of cystogenesis have been put forward. Among them are (1) the mechanosensory hypothesis of renal cilia function, (2) participation in signaling at focal adhesions and adherens junctions, (3) a role in the maintenance of planar cell polarity within the noncanonical Wnt signaling pathway, and (4) a role in centrosome-related functions of cell-cycle regulation. These hypotheses are discussed next (Figure 6).

Figure 6.
Figure 6.

Nephrocystins localize to different subcellular compartments in a cell cycle–dependent manner and participate in multiple signaling pathways together with other “cystoproteins” (proteins that are mutated in cystic kidney disease). Functional complexes that play a role in the planar cell polarity (PCP) pathway are highlighted for focal adhesion (A), adherens junction (B), cilium (C), basal body (D), centrosome (E), nucleus (F), mitotic spindle (G), and the Wnt pathways (H). Cystoproteins are shown on colored background and in bold type using blue for nephrocystins (NPHP), orange for BBS proteins, green for polycystins (PKD) and fibrocystin (PKHD1), and yellow for cystoproteins of renal cystic mouse models. Proteins that are not bold have been described in the context of the pathogenesis of cystic kidney disease (e.g., as a binding partner to a bona fide cystoprotein). Associated proteins with no known role in cystic kidney diseases are shown on gray background. Black dots connect proteins that directly interact. (A) Focal adhesions. (1) Nephrocystin-1 directly interacts with the focal adhesion adapter protein p130Cas (“crk-associated substrate”) (99,100,102), which is a major mediator of focal adhesion assembly, binds to focal adhesion kinase, and mediates stress fiber formation (149). Nephrocystin-1 competes for binding to p130Cas with the proto-oncogene products Src and Fyn (99). (2) Nephrocystin-1 is in a protein complex with the focal adhesion proteins Pyk2/Fak2 (focal adhesion kinase 2), tensin (98), and filamin A and B. Its overexpression leads to activation of extracellular signal–regulated kinases 1 and 2 (ERK1 and ERK2) (98). (3) In children with NPHP, overexpression of α5β1 integrin was described in proximal tubules, which most likely results from defective α6-integrin expression (150). (4) The knockout mouse models for tensin (151) and for the Rho GDIα gene (152) both exhibit an NPHP-like phenotype, thereby implicating further proteins of the focal adhesion signaling cascade in the pathogenesis of NPHP-like diseases. (B) Adherens junctions. (1) Nephrocystin-1 co-localizes with E-cadherin and p130Cas to adherens junctions. (2) The C-terminal half of nephrocystin, the “nephrocystin homology domain,” is able to promote nephrocystin self-association and epithelial adherens junctional targeting (100). (3) Disruption of this targeting leads to reduced transepithelial resistance (100). (4) Nephrocystin-4 is in a protein complex with nephrocystin-1, NPHP2/inversin, p130Cas, and Pyk2/Fak2 and has been localized to adherens junctions in confluent MDCK cells (101). (C) Primary cilia. Recently, the development of a unifying hypothesis of renal cystogenesis was established (72). This hypothesis states that proteins that, when mutated, cause renal cystic disease in humans, mice, or zebrafish are part of a functional module, as defined by their subcellular localization to primary cilia, basal bodies, or centrosomes. This applies to polycystin-1 and -2; fibrocystin/polyductin; nephrocystin-1, -2 (inversin), -3, -4, and -5; BBS-associated proteins; cystin; polaris; ALMS1; and many others. Because nephrocystins interact, they are represented here as the “nephrocystin complex.” On the basis of positional cloning, mutations in the inversin gene were identified as causing infantile NPHP (type 2) (17). This established a link between the pathogenesis of NPHP and disease mechanisms of PKD (17), in which nephrocystin-1 interacts with both inversin and β-tubulin. Because β-tubulin is a major component of primary cilia, this led to demonstration of co-localization of all three proteins in the primary renal cilia of epithelial cells (17). The complex also contains NPHP3, which is mutated in adolescent NPHP (type 3) and in the renal cystic mouse model pcy. The ciliary hypothesis of cystic kidney disease was confirmed by revealing that Nphp3 mRNA was expressed in kidney, retinal connecting cilia, ciliated bile ducts, and the node, which regulates left–right body axis in mice (18), and by identifying mutations in nephrocystin-5 (IQCB1), which co-localizes with calmodulin to primary cilia of renal epithelial cells and retinal connecting cilia (20). (D) Basal bodies. Basal bodies are short cylindrical arrays of microtubules and other proteins that are found at the base of cilia and that organize the assembly of the ciliary axoneme. They are analogous to centrosomes. Nephrocystins localize to the transition zone of basal bodies (111). Proteins that are mutated in BBS are components of the basal body transitional zone and are highly conserved in evolution. (E) Centrosomes. For a protein that is mutated in the related disease BBS4, it was shown that BBS4 is instrumental in recruiting proteins (e.g., PCM1) to the pericentrosomal matrix, confirming the role of centrosomal function in the pathogenesis of BBS (116). (F) Transcriptional programs. The transcription factor HNF1β regulates transcription of multiple genes that are mutated in cystic kidney disease–related genes (153). (G) Cell-cycle regulation. The hypotheses of functional involvement of the nephrocystin complex at focal adhesions and adherens junction on the one hand and the ciliary/centrosomal hypotheses on the other hand may be integrated by demonstration that different locations of the complex may predominate in a cell cycle–dependent manner. This is evidenced by the findings that inversin/nephrocystin-2 (17), nephrocystin-4 (101), and nephrocystin-6 (21) expression occurs in a cell cycle–dependent manner. Inversin exhibits a dynamic expression pattern in MDCK cells that show expression at centrosomes in early prophase, at spindle poles in metaphase and anaphase, and at the midbody in cells that undergo cytokinesis (133,154). Nephrocystin-4 was detected in MDCK cells at centrosomes of dividing cells and in polarized cells close at the cytoskeleton and in the vicinity of the cortical actin cytoskeleton, with co-localization of p130Cas, Pyk2, and β-catenin (101). (H) Wnt pathways. Recent data demonstrated that in renal tubules, inversin/NPHP2 may induce switching from the canonical to the noncanonical Wnt signaling pathway in response to flow sensing by primary cilia of renal tubular cells (104). It is thought that this function of inversin is important to maintain renal epithelial cell polarity (96). The hypothesis that the renal cystic disease phenotype is due to defects in the maintenance of planar cell polarity seems plausible for multiple reasons: (1) It would reconcile previous functional hypotheses, because focal adhesions, adherens junctions, cilia, centrosomes, basal bodies, and regulation of the cell cycle all play a pivotal role in the regulation and maintenance of planar cell polarity (155); (2) because planar cell polarity plays an important role in developmental morphogenesis and also in the regeneration of differentiated tissue, a defect in planar cell polarity may explain both the occurrence of cysts during organogenesis and degenerative cystogenesis as it occurs in NPHP; and (3) the mechanism of convergent extension, which may be central to renal tubular morphology, was shown to be disturbed in many renal cystic diseases (156). APC, adenomatous polyposis coli protein; APC2, anaphase promoting complex subunit 2; CBP, CREB-binding protein; CREB, cAMP response element–binding protein; CK1ε, casein kinase ε; DKK, Dickkopf-related protein; CK2, casein kinase II; GAP, RhoGTPase activating protein; GEF, guanine nucleotide exchange factor; GSK3, glycogen synthase kinase 3; JUNK, JUN kinase; PCM1, pericentriolar material 1; p150, p150glued/dynactin-1; PKC, protein kinase C; ROCK, Rho-associated protein kinase.

The Mechanosensory Hypothesis

On the basis of the initial finding that bending the primary cilium elicits Ca2+ influx (134–136), it was shown that cilia can act as mechanosensors to sense fluid movement in the kidney tubule, in cooperation with polycystins. In this model, polycystin-1 transmits the signal to polycystin-2, which is a TRP calcium channel (103). This produces sufficient Ca2+ influx to induce Ca2+ release from intracellular stores, which then regulates numerous signaling activities inside the cell that are linked to cell-cycle regulation. It is thought that defects in cell-cycle regulation may be ultimately responsible for the development of kidney cysts (103). In support of the ciliary hypothesis of cystic kidney diseases, a motor protein of the kinesin II family, KIF3A, which is involved in intraciliary transport, was shown to cause a murine renal cystic disease when mutated (113). Kramer-Zucker et al. (137) recently showed that cilia of larval zebrafish kidney tubules have a 9 + 2 configuration and are motile. Disruption of cilia structure or motility resulted in pronephric cyst formations, with left–right asymmetry defects. Despite many data in support of the ciliary hypothesis, some data are still hard to reconcile with this model; for example, the autosomal dominant variant of NPHP, MCKD2, is caused by mutations in uromodulin, which has so far not been detected in cilia, basal bodies, or centrosomes.

Focal Adhesion Hypothesis

When NPHP1 was first identified (15), we proposed a pathogenic hypothesis that tied in nephrocystin-1 with defects of cell–cell and cell–matrix signaling (102,138). This was based on the finding that nephrocystin-1 contains an SH3 domain, localizes to adherens junctions and focal adhesions of renal epithelial cells, and interacts with integral components of these structures, such as p130CAS (99,100). This “adherens junction/focal adhesion hypothesis” of NPHP pathogenesis (102,138) recently was partially reconciled with the “cilia/centrosome” hypothesis in an integrative hypothesis by showing that nephrocystin-4/nephroretinin in polarized epithelial cells co-localizes with β-catenin at cell–cell contact sites and to primary cilia, whereas in dividing cells, it localizes to centrosomes (101) (Figure 6, A and B).

The Wnt Pathway

Recent results on inversin/NPHP2 shed light on the mechanosensory hypothesis of bending of primary cilia by tubular flow. They have provided data on downstream signaling events that are necessary to maintain normal tubular development and morphology (104): In this model (Figure 6,C, F, and H) the canonical Wnt signaling occurs primarily through β-catenin–dependent pathways in the absence of tubular flow. Stimulation of the primary cilium by flow, however, increases expression of inversin, which then reduces levels of cytoplasmic disheveled through proteasomal degradation and subsequently switches off the canonical pathway by allowing activation of the β-catenin destruction complex (96). When inversin is defective (as in NPHP type 2), the canonical Wnt pathway will prevail and disrupt apical-basolateral polarity of the renal epithelium (96). Because planar cell polarity signaling is important for oriented cell division, it seems logical that Fisher et al. (139) recently were able to demonstrate abnormal orientation of the mitotic spindle in two different rodent models of cystic kidney disease.

Centrosomes

Nephrocystin-6, which is mutated in JBTS, is a component of the centrosomal proteome (86). In addition, BBS4 is instrumental in recruiting proteins to the pericentrosomal matrix, implicating the centrosome and its relation to cell-cycle control in the pathogenesis of BBS (117,140). The products of the genes mutated in the ciliopathy Meckel-Gruber syndrome MKS1 (81) and MKS3 (82) recently were shown to localize to basal bodies and centrosomes (141) (Figure 6D).

Cell Cycle

A balance between hyperproliferation and apoptosis may play an important role in the pathogenesis of cystic kidney diseases (Figure 6, F and G). For example, whereas in PKD, kidneys are grossly enlarged, in NPHP and BBS, kidney size remains normal and cysts grow at the expense of normal tissue (e vacuo). It seems that hyperproliferation may be the predominant mechanism in PKD-like diseases (142), whereas apoptosis is predominant in diseases of the NPHP and BBS group. A role of apoptosis was in fact confirmed in the Bbs2−/− and Bbs4−/− mouse models (143,144). Polycystin-1 and -2 signaling and the renal cystic phenotype may be linked by a function of these proteins in cell growth regulation. Polycystin-1 expression activates the JAK-STAT pathway, thereby upregulating p21(waf1) and inducing cell-cycle arrest in G0/G1 (145). The cell-cycle arrest requires polycystin-2. Involvement of polycystin-1/2 signaling in the JAK/STAT pathway might explain how mutations of either gene can result in dysregulated growth (145). Very recently, this hypothesis was confirmed by demonstration that two mouse models of PKD (jck and cpk) can be efficiently treated with the cyclin-dependent kinase inhibitor (R) roscovitine (146).

NPHP: Defects of Tissue Differentiation and Maintenance

It is striking that in renal cystic diseases (and in the associated extrarenal organ involvement), mutations of monogenic disease genes may lead to developmental defects (dysplasia), in which a structural organ defect is present at birth, but also to degenerative defects (degeneration), in which organ structure and function are normal at birth but deteriorate over time. Examples of this phenomenon from the side of cystic kidney disease are autosomal recessive PKD, in which there is a structural defect of the kidney present at birth, as opposed to NPHP, in which kidneys are normal at birth (with the exception of NPHP2) but degeneration leads to loss of renal function over the course of years. Regarding retinal involvement, NPHP can be associated with the developmental defect of retinal coloboma (lack of retinal tissue) in JBTS but also with the degenerative processes of tapetoretinal degeneration/retinitis pigmentosa (21,44,109). The joint occurrence of developmental and degenerative defect may be explained by the fact that many developmental transcriptional programs are reinitiated for mechanisms of tissue maintenance and repair. Because planar cell polarity plays an important role in developmental morphogenesis and also in the regeneration of differentiated tissue, a defect in planar cell polarity may explain both occurrence of cysts during organogenesis and degenerative cystogenesis as it occurs in NPHP.

Therapeutic Approaches to NPHP

No effective prophylaxis or treatment is available for NPHP. The only therapeutic options are supportive treatment once chronic renal failure has developed and dialysis and transplantation for terminal renal failure. An important future challenge will be the development of therapies that capitalize on what we have learned about the biology of NPHP and other cystic diseases of the kidney. Gattone et al. (106) recently showed that the renal cystic phenotype of pcy mice, which is the equivalent of human NPHP type 3, can be strongly mitigated or even reversed by treatment with the vasopressin V2 receptor antagonist OPC31260. Similar results were obtained using a pkd2 mouse model (147). This effect is thought to be mediated by a reduction in intracellular cAMP levels, a finding that awaits reconciliation with the ciliary/centrosome hypothesis of NPHP. In this context, it is interesting that nephrocystin-6 directly interacts with the transcription factor ATF4/CREB2, which plays a role in the regulation of intracellular cAMP levels (21). Additional therapeutic approaches are being considered for PKD (148).

Disclosures

None.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

References

  1. 1.↵
    Hildebrandt F, Otto E: Cilia and centrosomes: A unifying pathogenic concept for cystic kidney disease? Nat Rev Genet 6 : 928 –930, 2005
    OpenUrlCrossRefPubMed
  2. 2.↵
    Smith C, Graham J: Congenital medullary cysts of the kidneys with severe refractory anemia. Am J Dis Child 69 : 369 –377, 1945
    OpenUrlCrossRef
  3. 3.↵
    Fanconi G, Hanhart E, von Albertini A, Uhlinger E, Dolivo G, Prader A: Familial, juvenile nephronophthisis (idiopathic parenchymal contracted kidney) [in German]. Helv Pediatr Acta 6 : 1 –49, 1951
    OpenUrlPubMed
  4. 4.↵
    Hildebrandt F: Juvenile nephronophthisis. In: Pediatric Nephrology, edited by Harmon WE, Baltimore, Williams & Wilkins, 2004 , pp 665 –673
  5. 5.↵
    Gagnadoux MF, Bacri JL, Broyer M, Habib R: Infantile chronic tubulo-interstitial nephritis with cortical microcysts: Variant of nephronophthisis or new disease entity. Pediatr Nephrol 3 : 50 –55, 1989
    OpenUrlCrossRefPubMed
  6. 6.↵
    Hildebrandt F, Waldherr R, Kutt R, Brandis M: The nephronophthisis complex: Clinical and genetic aspects. Clin Investig 70 : 802 –808, 1992
    OpenUrlPubMed
  7. 7.↵
    Omran H, Fernandez C, Jung M, Haffner K, Fargier B, Villaquiran A, Waldherr R, Gretz N, Brandis M, Ruschendorf F, Reis A, Hildebrandt F: Identification of a new gene locus for adolescent nephronophthisis, on chromosome 3q22 in a large Venezuelan pedigree. Am J Hum Genet 66 : 118 –127, 2000
    OpenUrlCrossRefPubMed
  8. 8.↵
    Ala-Mello S, Kivivuori SM, Ronnholm KA, Koskimies O, Siimes MA: Mechanism underlying early anaemia in children with familial juvenile nephronophthisis. Pediatr Nephrol 10 : 578 –581, 1996
    OpenUrlCrossRefPubMed
  9. 9.↵
    Blowey DL, Querfeld U, Geary D, Warady BA, Alon U: Ultrasound findings in juvenile nephronophthisis. Pediatr Nephrol 10 : 22 –24, 1996
    OpenUrlCrossRefPubMed
  10. 9a.↵
    Hildebrandt F, Sayer JA, Jungers P, Grünfield J-P: Nephronophthisis—medullary cystic and medullary sponge kidney disease. In: Diseases of the Kidney and Urinary Tract, edited by Schrier WB, Philadelphia, Lippincott, Williams & Wilkins, 2007 , pp 478 –501
  11. 10.↵
    Waldherr R, Lennert T, Weber HP, Fodisch HJ, Scharer K: The nephronophthisis complex. A clinicopathologic study in children. Virchows Arch A Pathol Anat Histol 394 : 235 –254, 1982
    OpenUrlCrossRefPubMed
  12. 11.↵
    Zollinger HU, Gaboardi F, Imbasciati E, Lennert T: Nephronophthisis (medullary cystic disease of the kidney). A study using electron microscopy, immunofluorescence, and a review of the morphological findings. Helv Paediatr Acta 35 : 509 –530, 1980
    OpenUrlPubMed
  13. 12.↵
    Gardner KD Jr: Juvenile nephronophthisis and renal medullary cystic disease. Perspect Nephrol Hypertens 4 : 173 –185, 1976
    OpenUrlPubMed
  14. 13.↵
    Kleinknecht C: The inheritance of nephronophthisis. In: Inheritance of Kidney and Urinary Tract Diseases, Vol 9, edited by Avner ED, Boston, Kluwer Academic Publishers, 1989 , pp 299 –305
  15. 14.↵
    Steel BT, Lirenman DS, Battie CW: Nephronophthisis. Am J Med 68 : 531 –538, 1980
    OpenUrlCrossRefPubMed
  16. 15.↵
    Hildebrandt F, Otto E, Rensing C, Nothwang HG, Vollmer M, Adolphs J, Hanusch H, Brandis M: A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat Genet 17 : 149 –153, 1997
    OpenUrlCrossRefPubMed
  17. 16.↵
    Saunier S, Calado J, Heilig R, Silbermann F, Benessy F, Morin G, Konrad M, Broyer M, Gubler MC, Weissenbach J, Antignac C: A novel gene that encodes a protein with a putative src homology 3 domain is a candidate gene for familial juvenile nephronophthisis. Hum Mol Genet 6 : 2317 –2323, 1997
    OpenUrlCrossRefPubMed
  18. 17.↵
    Otto EA, Schermer B, Obara T, O’Toole JF, Hiller KS, Mueller AM, Ruf RG, Hoefele J, Beekmann F, Landau D, Foreman JW, Goodship JA, Strachan T, Kispert A, Wolf MT, Gagnadoux MF, Nivet H, Antignac C, Walz G, Drummond IA, Benzing T, Hildebrandt F: Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat Genet 34 : 413 –420, 2003
    OpenUrlCrossRefPubMed
  19. 18.↵
    Olbrich H, Fliegauf M, Hoefele J, Kispert A, Otto E, Volz A, Wolf MT, Sasmaz G, Trauer U, Reinhardt R, Sudbrak R, Antignac C, Gretz N, Walz G, Schermer B, Benzing T, Hildebrandt F, Omran H: Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis Nat Genet 34 : 455 –459, 2003
    OpenUrlCrossRefPubMed
  20. 19.↵
    Otto E, Hoefele J, Ruf R, Mueller AM, Hiller KS, Wolf MT, Schuermann MJ, Becker A, Birkenhager R, Sudbrak R, Hennies HC, Nurnberg P, Hildebrandt F: A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution. Am J Hum Genet 71 : 1167 –1171, 2002
    OpenUrl
  21. 20.↵
    Otto EA, Loeys B, Khanna H, Hellemans J, Sudbrak R, Fan S, Muerb U, O’Toole JF, Helou J, Attanasio M, Utsch B, Sayer JA, Lillo C, Jimeno D, Coucke P, De Paepe A, Reinhardt R, Klages S, Tsuda M, Kawakami I, Kusakabe T, Omran H, Imm A, Tippens M, Raymond PA, Hill J, Beales P, He S, Kispert A, Margolis B, Williams DS, Swaroop A, Hildebrandt F: Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet 37 : 282 –288, 2005
    OpenUrlCrossRefPubMed
  22. 21.↵
    Sayer JA, Otto EA, O’Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC, Helou J, Attanasio M, Fausett BV, Utsch B, Khanna H, Liu Y, Drummond I, Kawakami I, Kusakabe T, Tsuda M, Ma L, Lee H, Larson RG, Allen SJ, Wilkinson CJ, Nigg EA, Shou C, Lillo C, Williams DS, Hoppe B, Kemper MJ, Neuhaus T, Parisi MA, Glass IA, Petry M, Kispert A, Gloy J, Ganner A, Walz G, Zhu X, Goldman D, Nurnberg P, Swaroop A, Leroux MR, Hildebrandt F: The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 38 : 674 –681, 2006
    OpenUrlCrossRefPubMed
  23. 22.↵
    Hildebrandt F, Strahm B, Nothwang HG, Gretz N, Schnieders B, Singh-Sawhney I, Kutt R, Vollmer M, Brandis M: Molecular genetic identification of families with juvenile nephronophthisis type 1: Rate of progression to renal failure. APN Study Group. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Kidney Int 51 : 261 –269, 1997
    OpenUrlPubMed
  24. 23.↵
    Haider NB, Carmi R, Shalev H, Sheffield VC, Landau D: A Bedouin kindred with infantile nephronophthisis demonstrates linkage to chromosome 9 by homozygosity mapping. Am J Hum Genet 63 : 1404 –1410, 1998
    OpenUrlCrossRefPubMed
  25. 24.↵
    Gretz N: Rate of deterioration of renal function in juvenile nephronophthisis. Pediatr Nephrol 3 : 56 –60, 1989
    OpenUrlCrossRefPubMed
  26. 25.↵
    Christodoulou K, Tsingis M, Stavrou C, Eleftheriou A, Papapavlou P, Patsalis PC, Ioannou P, Pierides A, Constantinou Deltas C: Chromosome 1 localization of a gene for autosomal dominant medullary cystic kidney disease. Hum Mol Genet 7 : 905 –911, 1998
    OpenUrlCrossRefPubMed
  27. 26.↵
    Scolari F, Ghiggeri GM, Amoroso A, Caridi GL, Aridon P: Genetic heterogeneity for autosomal dominant medullary cystic kidney disease (ADMCKD) [Abstract]. J Am Soc Nephrol 9 : 393A , 1998
    OpenUrl
  28. 27.↵
    Potter DE, Holliday MA, Piel CF, Feduska NJ, Belzer FO, Salvatierra O Jr: Treatment of end-stage renal disease in children: A 15-year experience. Kidney Int 18 : 103 –109, 1980
    OpenUrlPubMed
  29. 28.↵
    Pistor K, Scharer K, Olbing H, Tamminen-Mobius T: Children with chronic renal failure in the Federal Republic of Germany: II. Primary renal diseases, age and intervals from early renal failure to renal death. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Clin Nephrol 23 : 278 –284, 1985
    OpenUrlPubMed
  30. 29.↵
    Cantani A, Bamonte G, Ceccoli D: Familial juvenile nephronophthisis. Clin Pediatr 25 : 90 –95, 1986
    OpenUrlCrossRefPubMed
  31. 30.
    Betts PR, Forest-Hay I: Juvenile nephronophthisis. Lancet 2 : 475 –478, 1973
    OpenUrlPubMed
  32. 31.↵
    Green A, Allos M, Donohoe J, Carmody M, Walshe J: Prevalence of hereditary renal disease. Ir Med J 83 : 11 –13, 1990
    OpenUrlPubMed
  33. 32.↵
    Warady BA, Hebert D, Sullivan EK, Alexander SR, Tejani A: Renal transplantation, chronic dialysis, and chronic renal insufficiency in children and adolescents. The 1995 Annual Report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 11 : 49 –64, 1997
    OpenUrlCrossRefPubMed
  34. 33.↵
    Avner ED: Medullary cystic disease and medullary sponge kidney. In: Primer on Kidney Diseases, edited by Greenberg A, Boston, Academic Press, 1994 , pp 255 –262
  35. 34.↵
    Senior B, Friedmann AI, Braudo JL: Juvenile familial nephropathy with tapetoretinal degeneration: A new oculorenal dystrophy. Am J Ophthalmol 52 : 625 –633, 1961
    OpenUrlCrossRefPubMed
  36. 35.↵
    Loken AC, Hanssen O, Halvorsen S, Jolster NJ: Hereditary renal dysplasia and blindness. Acta Paediatr 50 : 177 –184, 1961
    OpenUrlCrossRefPubMed
  37. 36.↵
    Saraiva JM, Baraitser M: Joubert syndrome: A review. Am J Med Genet 43 : 726 –731, 1992
    OpenUrlCrossRefPubMed
  38. 37.↵
    Valente EM, Marsh SE, Castori M, Dixon-Salazar T, Bertini E, Al-Gazali L, Messer J, Barbot C, Woods CG, Boltshauser E, Al-Tawari AA, Salpietro CD, Kayserili H, Sztriha L, Gribaa M, Koenig M, Dallapiccola B, Gleeson JG: Distinguishing the four genetic causes of Jouberts syndrome-related disorders. Ann Neurol 57 : 513 –519, 2005
    OpenUrlCrossRefPubMed
  39. 38.↵
    Saunier S et al.: Large deletions of the NPH1 region in Cogan syndrome (CS) associated with familial juvenile nephronophthisis (NPH) [Abstract]. Am J Hum Genet 61 : A346 , 1997
    OpenUrl
  40. 39.↵
    Baris H, Bejjani BA, Tan WH, Coulter DL, Martin JA, Storm AL, Burton BK, Saitta SC, Gajecka M, Ballif BC, Irons MB, Shaffer LG, Kimonis VE: Identification of a novel polymorphism: The duplication of the NPHP1 (nephronophthisis 1) gene. Am J Med Genet A 140 : 1876 –1879, 2006
    OpenUrlPubMed
  41. 40.↵
    Boichis H, Passwell J, David R, Miller H: Congenital hepatic fibrosis and nephronophthisis. A family study. Q J Med 42 : 221 –233, 1973
    OpenUrlPubMed
  42. 41.↵
    Mainzer F, Saldino RM, Ozonoff MB, Minagi H: Familial nephropathy associated with retinitis pigmentosa, cerebellar ataxia and skeletal abnormalities. Am J Med 49 : 556 –562, 1970
    OpenUrlPubMed
  43. 42.↵
    O’Toole JF, Otto E, Frishberg Y, Hildebrandt F: Retinitis pigmentosa and renal failure in a patient with mutations in inversin [Abstract]. J Am Soc Nephrol 15 : 215A , 2004
    OpenUrl
  44. 43.↵
    Contreras DB, Espinoza JS: Discussion clinica y anatomopatologica de enfermos que presentaron un problema diagnostico [in Spanish]. Pediatrica (Santiago) 3 : 271 –282, 1960
    OpenUrl
  45. 44.↵
    Saraux H, Dhermy P, Fontaine JL, Boulesteix J, Lasfargue G, Grenet P, N′ghiem M, Laplane R: Senior-Loken retino-tubular degeneration [in French]. Arch Ophtalmol Rev Gen Ophtalmol 30 : 683 –696, 1970
    OpenUrlPubMed
  46. 45.↵
    Medhioub M, Cherif D, Benessy F, Silbermann F, Gubler MC, Le Paslier D, Cohen D, Weissenbach J, Beckmann J, Antignac C: Refined mapping of a gene (NPH1) causing familial juvenile nephronophthisis and evidence for genetic heterogeneity. Genomics 22 : 296 –301, 1994
    OpenUrlCrossRefPubMed
  47. 46.↵
    Biersdorf WR: The clinical utility of the foveal electroretinogram: A review. Doc Ophthalmol 73 : 313 –325, 1989
    OpenUrlCrossRefPubMed
  48. 47.↵
    Joubert M, Eisenring JJ, Robb JP, Andermann F: Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology 19 : 813 –825, 1969
    OpenUrlFREE Full Text
  49. 48.
    Parisi MA, Dobyns WB: Human malformations of the midbrain and hindbrain: Review and proposed classification scheme. Mol Genet Metab 80 : 36 –53, 2003
    OpenUrlCrossRefPubMed
  50. 49.↵
    Gleeson JG, Keeler K, Parisi MA, Marsh SE, Chance PF, Glass IA, Graham Jr JM, Maria BL, Barkovich AJ, Dobyns WB: Molar tooth sign of the midbrain-hindbrain junction: Occurrence in multiple distinct syndromes. Am J Med Genet 125A : 125 –134, discussion 117, 2004
    OpenUrl
  51. 50.↵
    Castori M, Valente EM, Donati MA, Salvi S, Fazzi E, Procopio E, Galluccio T, Emma F, Dallapiccola B, Bertini E; Italian MTS Study Group: NPHP1 gene deletion is a rare cause of Joubert syndrome related disorders. J Med Genet 42 : e9 , 2005
    OpenUrlFREE Full Text
  52. 51.↵
    Utsch B, Sayer JA, Attanasio M, Pereira RR, Eccles M, Hennies HC, Otto EA, Hildebrandt F: Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome. Pediatr Nephrol 21 : 32 –35, 2006
    OpenUrlCrossRefPubMed
  53. 52.↵
    Parisi MA, Doherty D, Eckert ML, Shaw DW, Ozyurek H, Aysun S, Giray O, Al Swaid A, Al Shahwan S, Dohayan N, Bakhsh E, Indridason OS, Dobyns WB, Bennett CL, Chance PF, Glass IA: AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome. J Med Genet 43 : 334 –339, 2006
    OpenUrlAbstract/FREE Full Text
  54. 53.↵
    Valente EM, Silhavy JL, Brancati F, Barrano G, Krishnaswami SR, Castori M, Lancaster MA, Boltshauser E, Boccone L, Al-Gazali L, Fazzi E, Signorini S, Louie CM, Bellacchio E; International Joubert Syndrome Related Disorders Study Group; Bertini E, Dallapiccola B, Gleeson JG: Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat Genet 38 : 623 –625, 2006
    OpenUrlCrossRefPubMed
  55. 54.↵
    Ferland RJ, Eyaid W, Collura RV, Tully LD, Hill RS, Al-Nouri D, Al-Rumayyan A, Topcu M, Gascon G, Bodell A, Shugart YY, Ruvolo M, Walsh CA: Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 36 : 1008 –1013, 2004
    OpenUrlCrossRefPubMed
  56. 55.↵
    Dixon-Salazar T, Silhavy JL, Marsh SE, Louie CM, Scott LC, Gururaj A, Al-Gazali L, Al-Tawari AA, Kayserili H, Sztriha L, Gleeson JG: Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet 75 : 979 –987, 2004
    OpenUrlCrossRefPubMed
  57. 56.↵
    Betz R, Rensing C, Otto E, Mincheva A, Zehnder D, Lichter P, Hildebrandt F: Children with ocular motor apraxia type Cogan carry deletions in the gene (NPHP1) for juvenile nephronophthisis. J Pediatr 136 : 828 –831, 2000
    OpenUrlCrossRefPubMed
  58. 57.↵
    Mollet G, Salomon R, Gribouval O, Silbermann F, Bacq D, Landthaler G, Milford D, Nayir A, Rizzoni G, Antignac C, Saunier S: The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin. Nat Genet 32 : 300 –305, 2002
    OpenUrlCrossRefPubMed
  59. 58.↵
    Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, Rub U, Shattuck D, Salamon G, Kudo LC, Ou J, Lin DD, Salih MA, Kansu T, Al Dhalaan H, Al Zayed Z, MacDonald DB, Stigsby B, Plaitakis A, Dretakis EK, Gottlob I, Pieh C, Traboulsi EI, Wang Q, Wang L, Andrews C, Yamada K, Demer JL, Karim S, Alger JR, Geschwind DH, Deller T, Sicotte NL, Nelson SF, Baloh RW, Engle EC: Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science 304 : 1509 –1513, 2004
    OpenUrlAbstract/FREE Full Text
  60. 59.↵
    Saar K, Al-Gazali L, Sztriha L, Rueschendorf F, Nur-E-Kamal M, Reis A, Bayoumi R: Homozygosity mapping in families with Joubert syndrome identifies a locus on chromosome 9q34.3 and evidence for genetic heterogeneity. Am J Hum Genet 65 : 1666 –1671, 1999
    OpenUrlCrossRefPubMed
  61. 60.↵
    Keeler LC, Marsh SE, Leeflang EP, Woods CG, Sztriha L, Al-Gazali L, Gururaj A, Gleeson JG: Linkage analysis in families with Joubert syndrome plus oculo-renal involvement identifies the CORS2 locus on chromosome 11p12–q13.3. Am J Hum Genet 73 : 656 –662, 2003
    OpenUrlCrossRefPubMed
  62. 61.↵
    Delaney V, Mullaney J, Bourke E: Juvenile nephronophthisis, congenital hepatic fibrosis and retinal hypoplasia in twins. Q J Med 47 : 281 –290, 1978
    OpenUrlPubMed
  63. 62.
    Proesmans W, Van Damme B, Macken J: Nephronophthisis and tapetoretinal degeneration associated with liver fibrosis. Clin Nephrol 3 : 160 –164, 1975
    OpenUrlPubMed
  64. 63.↵
    Rayfield EJ, McDonald FD: Red and blonde hair in renal medullary cystic disease. Arch Intern Med 130 : 72 –75, 1972
    OpenUrlCrossRefPubMed
  65. 64.↵
    Mochizuki T, Saijoh Y, Tsuchiya K, Shirayoshi Y, Takai S, Taya C, Yonekawa H, Yamada K, Nihei H, Nakatsuji N, Overbeek PA, Hamada H, Yokoyama T: Cloning of inv, a gene that controls left/right asymmetry and kidney development. Nature 395 : 177 –181, 1998
    OpenUrlCrossRefPubMed
  66. 65.↵
    Morgan D, Turnpenny L, Goodship J, Dai W, Majumder K, Matthews L, Gardner A, Schuster G, Vien L, Harrison W, Elder FF, Penman-Splitt M, Overbeek P, Strachan T: Inversin, a novel gene in the vertebrate left-right axis pathway, is partially deleted in the inv mouse. Nat Genet 20 : 149 –156, 1998
    OpenUrlCrossRefPubMed
  67. 66.↵
    Igarashi P, Somlo S: Genetics and pathogenesis of polycystic kidney disease. J Am Soc Nephrol 13 : 2384 –2398, 2002
    OpenUrlFREE Full Text
  68. 67.↵
    Hirokawa N, Noda Y, Okada Y: Kinesin and dynein superfamily proteins in organelle transport and cell division. Curr Opin Cell Biol 10 : 60 –73, 1998
    OpenUrlCrossRefPubMed
  69. 68.↵
    McGrath J, Somlo S, Makova S, Tian X, Brueckner M: Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 114 : 61 –73, 2003
    OpenUrlCrossRefPubMed
  70. 69.↵
    Pennekamp P, Karcher C, Fischer A, Schweickert A, Skryabin B, Horst J, Blum M, Dworniczak B: The ion channel polycystin-2 is required for left-right axis determination in mice. Curr Biol 12 : 938 –943, 2002
    OpenUrlCrossRefPubMed
  71. 70.↵
    Alton DJ, McDonald P: Urographic findings in the Bardet-Biedl syndrome, formerly the Laurence-Moon-Biedl syndrome. Radiology 109 : 659 –663, 1973
    OpenUrlCrossRefPubMed
  72. 71.↵
    Green JS, Parfrey PS, Harnett JD, Farid NR, Cramer BC, Johnson G, Heath O, McManamon PJ, O’Leary E, Pryse-Phillips W: The cardinal manifestations of Bardet-Biedl syndrome, a form of Laurence-Moon-Biedl syndrome. N Engl J Med 321 : 1002 –1009, 1989
    OpenUrlCrossRefPubMed
  73. 72.↵
    Watnick T, Germino G: From cilia to cyst. Nat Genet 34 : 355 –356, 2003
    OpenUrlCrossRefPubMed
  74. 73.↵
    Badano JL, Katsanis N: Beyond Mendel: An evolving view of human genetic disease transmission. Nat Rev Genet 3 : 779 –789, 2002
    OpenUrlCrossRefPubMed
  75. 74.↵
    Donaldson MD, Warner AA, Trompeter RS, Haycock GB, Chantler C: Familial juvenile nephronophthisis, Jeune’s syndrome, and associated disorders. Arch Intern Med 60 : 426 –434, 1985
    OpenUrl
  76. 75.
    Jeune M, Beraud C, Carron R: Asphyxiating thoracic dystrophy with familial characteristics [in French]. Arch Fr Pediatr 12 : 886 –891, 1955
    OpenUrlPubMed
  77. 76.
    Amirou M, Bourdat-Michel G, Pinel N, Huet G, Gaultier J, Cochat P: Successful renal transplantation in Jeune syndrome type 2. Pediatr Nephrol 12 : 293 –294, 1998
    OpenUrlCrossRefPubMed
  78. 77.↵
    Sarimurat N, Elcioglu N, Tekant GT, Elicevik M, Yeker D: Jeune’s asphyxiating thoracic dystrophy of the newborn. Eur J Pediatr Surg 8 : 100 –101, 1998
    OpenUrlPubMed
  79. 78.↵
    Moudgil A, Bagga A, Kamil ES, Rimoin DL, Lachman RS, Cohen AH, Jordan SC: Nephronophthisis associated with Ellis-van Creveld syndrome. Pediatr Nephrol 12 : 20 –22, 1998
    OpenUrlCrossRefPubMed
  80. 79.↵
    Di Rocco M, Picco P, Arslanian A, Restagno G, Perfumo F, Buoncompagni A, Gattorno M, Borrone C: Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): A new syndrome Am J Med Genet 73 : 1 –4, 1997
    OpenUrlCrossRefPubMed
  81. 80.↵
    Marshall JD, Bronson RT, Collin GB, Nordstrom AD, Maffei P, Paisey RB, Carey C, Macdermott S, Russell-Eggitt I, Shea SE, Davis J, Beck S, Shatirishvili G, Mihai CM, Hoeltzenbein M, Pozzan GB, Hopkinson I, Sicolo N, Naggert JK, Nishina PM: New Alstrom syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med 165 : 675 –683, 2005
    OpenUrlCrossRefPubMed
  82. 81.↵
    Kyttala M, Tallila J, Salonen R, Kopra O, Kohlschmidt N, Paavola-Sakki P, Peltonen L, Kestila M: MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome. Nat Genet 38 : 155 –157, 2006
    OpenUrlCrossRefPubMed
  83. 82.↵
    Smith UM, Consugar M, Tee LJ, McKee BM, Maina EN, Whelan S, Morgan NV, Goranson E, Gissen P, Lilliquist S, Aligianis IA, Ward CJ, Pasha S, Punyashthiti R, Malik Sharif S, Batman PA, Bennett CP, Woods CG, McKeown C, Bucourt M, Miller CA, Cox P, Algazali L, Trembath RC, Torres VE, Attie-Bitach T, Kelly DA, Maher ER, Gattone VH 2nd, Harris PC, Johnson CA: The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat Genet 38 : 191 –196, 2006
    OpenUrlCrossRefPubMed
  84. 83.↵
    Baala L, Romano S, Khaddour R, Saunier S, Smith UM, Audollent S, Ozilou C, Faivre L, Laurent N, Foliguet B, Munnich A, Lyonnet S, Salomon R, Encha-Razavi F, Gubler MC, Boddaert N, de Lonlay P, Johnson CA, Vekemans M, Antignac C, Attie-Bitach T: The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am J Hum Genet 80 : 186 –194, 2007
    OpenUrlCrossRefPubMed
  85. 84.↵
    Collin GB, Marshall JD, Ikeda A, So WV, Russell-Eggitt I, Maffei P, Beck S, Boerkoel CF, Sicolo N, Martin M, Nishina PM, Naggert JK: Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstrom syndrome. Nat Genet 31 : 74 –78, 2002
    OpenUrlCrossRefPubMed
  86. 85.↵
    Hearn T, Renforth GL, Spalluto C, Hanley NA, Piper K, Brickwood S, White C, Connolly V, Taylor JF, Russell-Eggitt I, Bonneau D, Walker M, Wilson DI: Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome. Nat Genet 31 : 79 –83, 2002
    OpenUrlPubMed
  87. 86.↵
    Andersen JS, Wilkinson CJ, Mayor T, Mortensen P, Nigg EA, Mann M: Proteomic characterization of the human centrosome by protein correlation profiling. Nature 426 : 570 –574, 2003
    OpenUrlCrossRefPubMed
  88. 87.↵
    Hearn T, Spalluto C, Phillips VJ, Renforth GL, Copin N, Hanley NA, Wilson DI: Subcellular localization of ALMS1 supports involvement of centrosome and basal body dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. Diabetes 54 : 1581 –1587, 2005
    OpenUrlAbstract/FREE Full Text
  89. 88.↵
    Alstrom CH, Hallgren B, Nilsson LB, Asander H: Retinal degeneration combined with obesity, diabetes mellitus and neurogenous deafness: A specific syndrome (not hitherto described) distinct from the Laurence-Moon-Biedl syndrome. A clinical endocrinological and genetic examination based on a large pedigree. Acta Psychiatr Neurol Scand 34[Suppl 129] : 1 –35, 1959
    OpenUrl
  90. 89.↵
    Goldstein JL, Fialkow PJ: The Alstrom syndrome. Report of three cases with further delineation of the clinical, pathophysiological, and genetic aspects of the disorder. Medicine (Baltimore) 52 : 53 –71, 1973
    OpenUrlPubMed
  91. 90.↵
    Tsimaratos M, Sarles J, Sigaudy S, Philip N: Renal and retinal involvement in the Sensenbrenner syndrome. Am J Med Genet 77 : 337 , 1998
    OpenUrlCrossRefPubMed
  92. 91.↵
    Costet C, Betis F, Berard E, Tsimaratos M, Sigaudy S, Antignac C, Gastaud P: Pigmentosum retinis and tubulo-interstitial nephronophtisis in Sensenbrenner syndrome: A case report [in French]. J Fr Ophtalmol 23 : 158 –160, 2000
    OpenUrlPubMed
  93. 92.↵
    Kumada S, Hayashi M, Arima K, Nakayama H, Sugai K, Sasaki M, Kurata K, Nagata M: Renal disease in Arima syndrome is nephronophthisis as in other Joubert-related cerebello-oculo-renal syndromes. Am J Med Genet A 131 : 71 –76, 2004
    OpenUrlPubMed
  94. 93.
    Satran D, Pierpont ME, Dobyns WB: Cerebello-oculo-renal syndromes including Arima, Senior-Loken and COACH syndromes: More than just variants of Joubert syndrome. Am J Med Genet 86 : 459 –469, 1999
    OpenUrlCrossRefPubMed
  95. 94.↵
    Chance PF, Cavalier L, Satran D, Pellegrino JE, Koenig M, Dobyns WB: Clinical nosologic and genetic aspects of Joubert and related syndromes. J Child Neurol 14 : 660 –666, discussion 669–672, 1999
    OpenUrlCrossRefPubMed
  96. 95.↵
    Ala-Mello S, Kaariainen H, Koskimies O: Nephronophthisis and ulcerative colitis in siblings: A new association. Pediatr Nephrol 16 : 507 –509, 2001
    OpenUrlCrossRefPubMed
  97. 96.↵
    Germino GG: Linking cilia to Wnts. Nat Genet 37 : 455 –457, 2005
    OpenUrlCrossRefPubMed
  98. 97.↵
    Otto E, Kispert A, Schatzle, Lescher B, Rensing C, Hildebrandt F: Nephrocystin: Gene expression and sequence conservation between human, mouse, and Caenorhabditis elegans. J Am Soc Nephrol 11 : 270 –282, 2000
    OpenUrlAbstract/FREE Full Text
  99. 98.↵
    Benzing T, Gerke P, Hopker K, Hildebrandt F, Kim E, Walz G: Nephrocystin interacts with Pyk2, p130(Cas), and tensin and triggers phosphorylation of Pyk2. Proc Natl Acad Sci U S A 98 : 9784 –9789, 2001
    OpenUrlAbstract/FREE Full Text
  100. 99.↵
    Donaldson JC, Dempsey PJ, Reddy S, Bouton AH, Coffey RJ, Hanks SK: Crk-associated substrate p130(Cas) interacts with nephrocystin and both proteins localize to cell-cell contacts of polarized epithelial cells. Exp Cell Res 256 : 168 –178, 2000
    OpenUrlCrossRefPubMed
  101. 100.↵
    Donaldson JC, Dise RS, Ritchie MD, Hanks SK: Nephrocystin-conserved domains involved in targeting to epithelial cell-cell junctions, interaction with filamins, and establishing cell polarity. J Biol Chem 277 : 29028 –29035, 2002
    OpenUrlAbstract/FREE Full Text
  102. 101.↵
    Mollet G, Silbermann F, Delous M, Salomon R, Antignac C, Saunier S: Characterization of the nephrocystin/nephrocystin-4 complex and subcellular localization of nephrocystin-4 to primary cilia and centrosomes. Hum Mol Genet 14 : 645 –656, 2005
    OpenUrlCrossRefPubMed
  103. 102.↵
    Hildebrandt F, Otto E: Molecular genetics of nephronophthisis and medullary cystic kidney disease. J Am Soc Nephrol 11 : 1753 –1761, 2000
    OpenUrlAbstract/FREE Full Text
  104. 103.↵
    Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J: Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33 : 129 –137, 2003
    OpenUrlCrossRefPubMed
  105. 104.↵
    Simons M, Gloy J, Ganner A, Bullerkotte A, Bashkurov M, Kronig C, Schermer B, Benzing T, Cabello OA, Jenny A, Mlodzik M, Polok B, Driever W, Obara T, Walz G: Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet 37 : 537 –543, 2005
    OpenUrlCrossRefPubMed
  106. 105.↵
    Okada Y, Nonaka S, Tanaka Y, Saijoh Y, Hamada H, Hirokawa N: Abnormal nodal flow precedes situs inversus in iv and inv mice. Mol Cell 4 : 459 –468, 1999
    OpenUrlCrossRefPubMed
  107. 106.↵
    Gattone VH 2nd, Wang X, Harris PC, Torres VE: Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med 9 : 1323 –1326, 2003
    OpenUrlCrossRefPubMed
  108. 107.↵
    Schuermann MJ, Otto E, Becker A, Saar K, Ruschendorf F, Polak BC, Ala-Mello S, Hoefele J, Wiedensohler A, Haller M, Omran H, Nurnberg P, Hildebrandt F: Mapping of gene loci for nephronophthisis type 4 and Senior-Loken syndrome, to chromosome 1p36. Am J Hum Genet 70 : 1240 –1246, 2002
    OpenUrlCrossRefPubMed
  109. 108.↵
    Wolf MT, Lee J, Panther F, Otto EA, Guan KL, Hildebrandt F: Expression and phenotype analysis of the nephrocystin-1 and nephrocystin-4 homologs in Caenorhabditis elegans. J Am Soc Nephrol 16 : 676 –687, 2005
    OpenUrlAbstract/FREE Full Text
  110. 109.↵
    Chang B, Khanna H, Hawes N, Jimeno D, He S, Lillo C, Parapuram SK, Cheng H, Scott A, Hurd RE, Sayer JA, Otto EA, Attanasio M, O’Toole JF, Jin G, Shou C, Hildebrandt F, Williams DS, Heckenlively JR, Swaroop A: In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum Mol Genet 15 : 1847 –1857, 2006
    OpenUrlCrossRefPubMed
  111. 110.↵
    den Hollander AI, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, Zonneveld MN, Strom TM, Meitinger T, Brunner HG, Hoyng CB, van den Born LI, Rohrschneider K, Cremers FP: Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet 79 : 556 –561, 2006
    OpenUrlCrossRefPubMed
  112. 110a.↵
    Bisgrove BW, Yost HJ: The roles of cilia in developmental disorders and diseases. Development 133 : 4131 –4143, 2006
    OpenUrlAbstract/FREE Full Text
  113. 111.↵
    Fliegauf M, Horvath J, von Schnakenburg C, Olbrich H, Muller D, Thumfart J, Schermer B, Pazour GJ, Neumann HP, Zentgraf H, Benzing T, Omran H: Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia. J Am Soc Nephrol 17 : 2424 –2433, 2006
    OpenUrlAbstract/FREE Full Text
  114. 112.↵
    Kozminski KG, Johnson KA, Forscher P, Rosenbaum JL: A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc Natl Acad Sci U S A 90 : 5519 –5523, 1993
    OpenUrlAbstract/FREE Full Text
  115. 113.↵
    Lin F, Hiesberger T, Cordes K, Sinclair AM, Goldstein LS, Somlo S, Igarashi P: Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci U S A 100 : 5286 –5291, 2003
    OpenUrlAbstract/FREE Full Text
  116. 114.↵
    Pazour GJ, Dickert BL, Witman GB: The DHC1b (DHC2) isoform of cytoplasmic dynein is required for flagellar assembly. J Cell Biol 144 : 473 –481, 1999
    OpenUrlAbstract/FREE Full Text
  117. 115.↵
    Benzing T, Walz G: Cilium-generated signaling: A cellular GPS? Curr Opin Nephrol Hypertens 15 : 245 –249, 2006
    OpenUrlCrossRefPubMed
  118. 116.↵
    Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, Kim JC, Ross AJ, Eichers ER, Teslovich TM, Mah AK, Johnsen RC, Cavender JC, Lewis RA, Leroux MR, Beales PL, Katsanis N: Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425 : 628 –633, 2003
    OpenUrlCrossRefPubMed
  119. 117.↵
    Badano JL, Teslovich TM, Katsanis N: The centrosome in human genetic disease. Nat Rev Genet 6 : 194 –205, 2005
    OpenUrlCrossRefPubMed
  120. 118.↵
    Barr MM, DeModena J, Braun D, Nguyen CQ, Hall DH, Sternberg PW: The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway. Curr Biol 11 : 1341 –1346, 2001
    OpenUrlCrossRefPubMed
  121. 119.↵
    Bae YK, Qin H, Knobel KM, Hu J, Rosenbaum JL, Barr MM: General and cell-type specific mechanisms target TRPP2/PKD-2 to cilia. Development 133 : 3859 –3870, 2006
    OpenUrlAbstract/FREE Full Text
  122. 120.↵
    Jauregui AR, Barr MM: Functional characterization of the C. elegans nephrocystins NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors. Exp Cell Res 305 : 333 –342, 2005
    OpenUrlCrossRefPubMed
  123. 121.↵
    Winkelbauer ME, Schafer JC, Haycraft CJ, Swoboda P, Yoder BK: The C. elegans homologs of nephrocystin-1 and nephrocystin-4 are cilia transition zone proteins involved in chemosensory perception. J Cell Sci 118 : 5575 –5587, 2005
    OpenUrlAbstract/FREE Full Text
  124. 122.↵
    Blacque OE, Reardon MJ, Li C, McCarthy J, Mahjoub MR, Ansley SJ, Badano JL, Mah AK, Beales PL, Davidson WS, Johnsen RC, Audeh M, Plasterk RH, Baillie DL, Katsanis N, Quarmby LM, Wicks SR, Leroux MR: Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. Genes Dev 18 : 1630 –1642, 2004
    OpenUrlAbstract/FREE Full Text
  125. 123.↵
    Li JB, Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, Li H, Blacque OE, Li L, Leitch CC, Lewis RA, Green JS, Parfrey PS, Leroux MR, Davidson WS, Beales PL, Guay-Woodford LM, Yoder BK, Stormo GD, Katsanis N, Dutcher SK: Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117 : 541 –552, 2004
    OpenUrlCrossRefPubMed
  126. 124.↵
    Fan Y, Esmail MA, Ansley SJ, Blacque OE, Boroevich K, Ross AJ, Moore SJ, Badano JL, May-Simera H, Compton DS, Green JS, Lewis RA, van Haelst MM, Parfrey PS, Baillie DL, Beales PL, Katsanis N, Davidson WS, Leroux MR: Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat Genet 36 : 989 –993, 2004
    OpenUrlCrossRefPubMed
  127. 125.↵
    Chiang AP, Nishimura D, Searby C, Elbedour K, Carmi R, Ferguson AL, Secrist J, Braun T, Casavant T, Stone EM, Sheffield VC: Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3). Am J Hum Genet 75 : 475 –484, 2004
    OpenUrlCrossRefPubMed
  128. 126.↵
    Mykytyn K, Sheffield VC: Establishing a connection between cilia and Bardet-Biedl Syndrome. Trends Mol Med 10 : 106 –109, 2004
    OpenUrlCrossRefPubMed
  129. 127.↵
    Efimenko E, Bubb K, Mak HY, Holzman T, Leroux MR, Ruvkun G, Thomas JH, Swoboda P: Analysis of xbx genes in C. elegans. Development 132 : 1923 –1934, 2005
    OpenUrlAbstract/FREE Full Text
  130. 128.↵
    Schermer B, Hopker K, Omran H, Ghenoiu C, Fliegauf M, Fekete A, Horvath J, Kottgen M, Hackl M, Zschiedrich S, Huber TB, Kramer-Zucker A, Zentgraf H, Blaukat A, Walz G, Benzing T: Phosphorylation by casein kinase 2 induces PACS-1 binding of nephrocystin and targeting to cilia. EMBO J 24 : 4415 –4424, 2005
    OpenUrlAbstract/FREE Full Text
  131. 129.↵
    Pazour GJ, Rosenbaum JL: Intraflagellar transport and cilia-dependent diseases. Trends Cell Biol 12 : 551 –555, 2002
    OpenUrlCrossRefPubMed
  132. 130.↵
    Hirokawa N, Takemura R: Biochemical and molecular characterization of diseases linked to motor proteins. Trends Biochem Sci 28 : 558 –565, 2003
    OpenUrlCrossRefPubMed
  133. 131.↵
    Tanaka T, Serneo FF, Higgins C, Gambello MJ, Wynshaw-Boris A, Gleeson JG: Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration. J Cell Biol 165 : 709 –721, 2004
    OpenUrlAbstract/FREE Full Text
  134. 132.↵
    Fath MA, Mullins RF, Searby C, Nishimura DY, Wei J, Rahmouni K, Davis RE, Tayeh MK, Andrews M, Yang B, Sigmund CD, Stone EM, Sheffield VC: Mkks-null mice have a phenotype resembling Bardet-Biedl Syndrome. Hum Mol Genet 14 : 1109 –1118, 2005
    OpenUrlCrossRefPubMed
  135. 133.↵
    Nurnberger J, Bacallao RL, Phillips CL: Inversin forms a complex with catenins and N-cadherin in polarized epithelial cells. Mol Biol Cell 13 : 3096 –3106, 2002
    OpenUrlAbstract/FREE Full Text
  136. 134.↵
    Praetorius HA, Spring KR: Bending the MDCK cell primary cilium increases intracellular calcium. J Membr Biol 184 : 71 –79, 2001
    OpenUrlCrossRefPubMed
  137. 135.
    Praetorius HA, Praetorius J, Nielsen S, Frokiaer J, Spring KR: Beta1-integrins in the primary cilium of MDCK cells potentiate fibronectin-induced Ca2+ signaling. Am J Physiol Renal Physiol 287 : F969 –F978, 2004
    OpenUrlCrossRefPubMed
  138. 136.↵
    Praetorius HA, Spring KR: The renal cell primary cilium functions as a flow sensor. Curr Opin Nephrol Hypertens 12 : 517 –520, 2003
    OpenUrlCrossRefPubMed
  139. 137.↵
    Kramer-Zucker AG, Olale F, Haycraft CJ, Yoder BK, Schier AF, Drummond IA: Cilia-driven fluid flow in the zebrafish pronephros, brain and Kupffer’s vesicle is required for normal organogenesis. Development 132 : 1907 –1921, 2005
    OpenUrlAbstract/FREE Full Text
  140. 138.↵
    Hildebrandt F: Identification of a gene for nephronophthisis. Nephrol Dial Transplant 13 : 1334 –1336, 1998
    OpenUrlCrossRefPubMed
  141. 139.↵
    Fischer E, Legue E, Doyen A, Nato F, Nicolas JF, Torres V, Yaniv M, Pontoglio M: Defective planar cell polarity in polycystic kidney disease. Nat Genet 38 : 21 –23, 2006
    OpenUrlCrossRefPubMed
  142. 140.↵
    Kim JC, Badano JL, Sibold S, Esmail MA, Hill J, Hoskins BE, Leitch CC, Venner K, Ansley SJ, Ross AJ, Leroux MR, Katsanis N, Beales PL: The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat Genet 36 : 462 –470, 2004
    OpenUrlCrossRefPubMed
  143. 141.↵
    Dawe HR, Smith UM, Cullinane AR, Gerrelli D, Cox P, Badano JL, Blair-Reid S, Sriram N, Katsanis N, Attie-Bitach T, Afford SC, Copp AJ, Kelly DA, Gull K, Johnson CA: The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. Hum Mol Genet 16 : 173 –186, 2007
    OpenUrlCrossRefPubMed
  144. 142.↵
    Ong AC, Harris PC: Molecular pathogenesis of ADPKD: The polycystin complex gets complex. Kidney Int 67 : 1234 –1247, 2005
    OpenUrlCrossRefPubMed
  145. 143.↵
    Nishimura DY, Fath M, Mullins RF, Searby C, Andrews M, Davis R, Andorf JL, Mykytyn K, Swiderski RE, Yang B, Carmi R, Stone EM, Sheffield VC: Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin. Proc Natl Acad Sci U S A 101 : 16588 –16593, 2004
    OpenUrlAbstract/FREE Full Text
  146. 144.↵
    Mykytyn K, Mullins RF, Andrews M, Chiang AP, Swiderski RE, Yang B, Braun T, Casavant T, Stone EM, Sheffield VC: Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly. Proc Natl Acad Sci U S A 101 : 8664 –8669, 2004
    OpenUrlAbstract/FREE Full Text
  147. 145.↵
    Bhunia AK, Piontek K, Boletta A, Liu L, Qian F, Xu PN, Germino FJ, Germino GG: PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell 109 : 157 –168, 2002
    OpenUrlCrossRefPubMed
  148. 146.↵
    Bukanov NO, Smith LA, Klinger KW, Ledbetter SR, Ibraghimov-Beskrovnaya O: Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine. Nature 444 : 949 –952, 2006
    OpenUrlCrossRefPubMed
  149. 147.↵
    Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH 2nd: Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med 10 : 363 –364, 2004
    OpenUrlCrossRefPubMed
  150. 148.↵
    Torres VE, Harris PC: Mechanisms of disease: Autosomal dominant and recessive polycystic kidney diseases. Nat Clin Pract Nephrol 2 : 40 –55; quiz 55, 2006
    OpenUrlCrossRefPubMed
  151. 149.↵
    Brugge JS: Casting light on focal adhesions. Nat Genet 19 : 309 –311, 1998
    OpenUrlCrossRefPubMed
  152. 150.↵
    Rahilly MA, Fleming S: Abnormal integrin receptor expression in two cases of familial nephronophthisis. Histopathology 26 : 345 –349, 1995
    OpenUrlPubMed
  153. 151.↵
    Lo SH, Yu QC, Degenstein L, Chen LB, Fuchs E: Progressive kidney degeneration in mice lacking tensin. J Cell Biol 136 : 1349 –1361, 1997
    OpenUrlAbstract/FREE Full Text
  154. 152.↵
    Togawa A, Miyoshi J, Ishizaki H, Tanaka M, Takakura A, Nishioka H, Yoshida H, Doi T, Mizoguchi A, Matsuura N, Niho Y, Nishimune Y, Nishikawa S, Takai Y: Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIalpha. Oncogene 18 : 5373 –5380, 1999
    OpenUrlCrossRefPubMed
  155. 153.↵
    Hiesberger T, Shao X, Gourley E, Reimann A, Pontoglio M, Igarashi P: Role of the hepatocyte nuclear factor-1beta (HNF-1beta) C-terminal domain in Pkhd1 (ARPKD) gene transcription and renal cystogenesis. J Biol Chem 280 : 10578 –10586, 2005
    OpenUrlAbstract/FREE Full Text
  156. 154.↵
    Morgan D, Eley L, Sayer J, Strachan T, Yates LM, Craighead AS, Goodship JA: Expression analyses and interaction with the anaphase promoting complex protein Apc2 suggest a role for inversin in primary cilia and involvement in the cell cycle. Hum Mol Genet 11 : 3345 –3350, 2002
    OpenUrlCrossRefPubMed
  157. 155.↵
    Keller R: Shaping the vertebrate body plan by polarized embryonic cell movements. Science 298 : 1950 –1954, 2002
    OpenUrlAbstract/FREE Full Text
  158. 156.↵
    Ross AJ, May-Simera H, Eichers ER, Kai M, Hill J, Jagger DJ, Leitch CC, Chapple JP, Munro PM, Fisher S, Tan PL, Phillips HM, Leroux MR, Henderson DJ, Murdoch JN, Copp AJ, Eliot MM, Lupski JR, Kemp DT, Dollfus H, Tada M, Katsanis N, Forge A, Beales PL: Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat Genet 37 : 1135 –1140, 2005
    OpenUrlCrossRefPubMed
  159. 157.↵
    Saunier S, Salomon R, Antignac C: Nephronophthisis. Curr Opin Genet Dev 15 : 324 –331, 2005
    OpenUrlCrossRefPubMed
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Nephronophthisis-Associated Ciliopathies
Friedhelm Hildebrandt, Weibin Zhou
JASN Jun 2007, 18 (6) 1855-1871; DOI: 10.1681/ASN.2006121344
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