Autosomal Dominant Progressive Nephropathy with Deafness: Linkage to a New Locus on Chromosome 11q24
Sunil Prakash*,
Ki Wha Chung,
Srish Sinha,
Michael Barmada,
Demetrius Ellis,
Robert E. Ferrell,
David N. Finegold,,
Parmjeet Singh Randhawa,
Amit Dinda¶ and
Abhay Vats
*Department of Nephrology, Northern Railway Central Hospital, New Delhi, India; Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pennsylvania; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and ¶Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Correspondence to Dr. Abhay Vats, Children’s Hospital of Pittsburgh, Division of Pediatric Nephrology, 3705 Fifth Avenue, Pittsburgh, PA 15213. Phone: 412-692-5182; Fax: 412-692-7443;
ABSTRACT. Focal segmental glomerulosclerosis (FSGS) and Alportsyndrome (AS) are two major causes of end-stage renal disease(ESRD). A few families with autosomal dominant FSGS have beenreported with linkage to chromosome 19q13 or 11q22, while ASis usually linked to mutations in type IV collagen (COL4) subunitgenes. A phenotype resembling AS may also be seen with myosinheavy chain-9 (MYH9) gene mutations. This study ascertaineda multigeneration family (CHP-177) with clinical aspects ofboth FSGS and AS where we identified a new locus for the trait.A genome-wide scan was performed with 400 markers, and finemapping was performed for chromosome 11 markers. Data were analyzedby GENEHUNTER and VITESSE under various models. CHP-177 is a39-member kindred residing near New Delhi, India, with sevenaffecteds and showed male-to-male transmission. Two membershad ESRD. Renal biopsies showed both FSGS lesions and thin glomerularbasement membranes. Five of the affecteds also had sensorineuraldeafness, which involved both low and high frequency in somemembers. The AS loci, i.e., COL4A3/COL4A4 and MYH9 (LOD scores:-6.1 and -4.3, respectively) and FSGS loci, on 19q13 and 11q22,were excluded from linkage. A significant evidence of linkagewas observed for 11q24 region, with a multipoint LOD (z-score)of 3.2 for marker D11S4464 at = 0. The z-1 confidence intervalfor the linked region spans a genetic distance of 7 cM. Thisstudy thus reports an autosomal dominant nephropathy with featuresof both FSGS and AS in which linkage to currently known locifor such phenotypes was excluded and a new locus on 11q24 wasidentified. The findings suggest further locus heterogeneityfor the autosomal dominant nephropathy phenotype. E-mail: abhay.vats@chp.edu
Strong evidence of genetic contributions for both disease developmentand progression is emerging for many renal diseases that aremajor public health problems and often lead to end-stage renaldisease (ESRD) (1). Several genes have been identified for manysuch progressive nephropathies, i.e., focal segmental glomerulosclerosis(FSGS), nail patella syndrome, as well as Alport syndrome (AS),and their variants (2–5). FSGS (MIM 603278) is usuallycharacterized by significant proteinuria and generalized edema.Currently known loci for FSGS are located on chromosomes 1q25,11q22, and 19q13 (2,4,6-9). In contrast to FSGS, AS is associatedwith hematuria, deafness, and characteristic ultrastructuralabnormalities of the glomerular basement membrane (GBM) (5,10).AS also displays considerable phenotypic and genetic heterogeneitywith the classic X-linked forms accounting for almost 85% ofthe cases, and the remaining 15% of cases showing autosomalinheritance (11–14). X-linked AS (MIM 301050) is associatedwith type IV collagen alpha 5 chain (COL4A5) mutations, whilemutations in alpha 3 chain (COL4A3) and alpha 4 chain (COL4A4)genes, located on chromosome 2q35-q37, have been found in casesof both autosomal recessive (MIM 203780) and dominant (MIM 104200)AS (12–16). Also, mutations in myosin heavy chain-9 nonmusclegene (MYH9) cause Epstein and Fechtner syndromes, which canbe associated with an autosomal dominant nephropathy that hassome features of AS (17,18). Thus the autosomal dominant nephropathyphenotype shows significant genetic heterogeneity. In this study,we describe an Asian Indian family with autosomal dominant progressivenephropathy, with features of both FSGS and AS, where geneticlinkage was excluded for various currently known candidate genesand a new locus was found on chromosome 11.
Ascertainment Criteria
Evaluation of CHP Family #177 members (pedigree shown in Figure 1)included a complete history, renal, hematologic and liverfunction tests, urinalysis, audiometric and ophthalmologic evaluations,radiologic and renal histologic studies. Asymptomatic individualswere examined for proteinuria and hematuria with qualitativeurinalysis, and selected individuals were also studied withaudiometry. Family members were classified as affected if theyhad ESRD requiring dialysis or renal transplantation or hadelevated blood urea nitrogen (BUN) and serum creatinine (SCr)or had hematuria (>10 RBC/hpf) and/or > 2+ proteinuriaby qualitative urinalysis, with or without hearing loss, inthe absence of other systemic diseases that are likely to leadto proteinuria or hematuria. They were classified as unaffectedif they were over 12 yr of age and had no hearing loss or detectablehematuria or proteinuria on qualitative urinalysis and werenormotensive or were unrelated married-in spouses. They werecategorized as unknown if: (a) they had hearing loss on audiometrybut had no urinary or renal function anomalies, or (b) no clinicalinformation was available, or (c) were less than 12 yr of ageand had no hearing, urinary or renal function anomalies. IndividualGPID III:20 was classified as unknown because she showed persistentlow-grade proteinuria at a young age but no other symptoms.
Figure 1. Pedigree of CHP Family #177. The open symbols stand for unaffected males () and unaffected females (). The filled symbols represent affected males () and affected females (•). The symbol represents deceased family members with unknown affection status. The numbers below each symbol refer to generation and person ID (GPID), which is also shown in Table 1. Half-filled symbols indicate unknown affection status. The stars indicate the persons whose DNA was used for genome-wide scan. Alleles within parenthesis were inferred.
Table 1. Clinical characteristics of CHP Family #177a
DNA Isolation and Genotyping
High–molecular weight genomic DNA was isolated from EDTAwhole blood by a salting-out procedure as previously reported(19,20). These studies were performed after obtaining informedconsent and were approved by the human rights committee of theChildren’s Hospital of Pittsburgh and Railway Hospital,New Delhi. Figure 1 identifies the pedigree members whose genomicDNA was used for these studies. Fluorescence genotyping wascarried out by NHLBI mammalian genotyping service facilitiesat Marshfield Clinics using approximately 400 microsatellitemarkers of screening set 10, which provided an average spacingof 9 cM across the genome (http://www.marshfieldclinic.org/research/genetics/sets/Set10ScreenFrames.htm).The PCR for fine mapping was performed on Techne thermocycler(Techne Inc, Princeton, NJ), and PCR products were resolvedon ABI-3700 capillary analyzer (Applied Biosystems, Foster City,CA) located in Center for Human Genetics and Integrative Biologyof the University of Pittsburgh (19). The data were analyzedby GENOTYPER program (version 3.7, Applera Corp, Norwalk, CT)and entered in PROGENY2000 database management system (ProgenySoftware, South Bend, IN). The following fluorescent dye–labeledmarkers were obtained from Research Genetics/Invitrogen (Carlsbad,CA) and used for fine mapping of the chromosome 11q24 region:D11S2371, D11S2002, D11S2000, D1S1986, D11S908, D11S1998, D11S4460,D11S95, D11S4464, D11S1328, D11S934, D11S1304, D11S969.
Power Studies
A visual inspection of the pedigree suggested autosomal dominantinheritance. The maximum attainable LOD (the log of the oddsof linkage) score for the pedigree was obtained by computersimulation studies with the SLINK program (21). For these simulations,the disease was assumed to be autosomal dominant with an allelefrequency of 0.0001. Assuming a four-allele system with equalfrequencies, simulations used a 5% recombination with the diseaselocus and various penetrance values ranging from 0.7 to 0.99.A set of 1000 iterations was generated, and maximum attainableLOD score was calculated using MSIM for various theta.
Linkage Analysis
The genotyping data were assessed by PEDCHECK program to identifyand correct Mendelian errors (22). The linkage was calculatedunder a dominant model with penetrance ranging from 0.8 to 0.99,no phenocopies, and assuming a disease allele frequency of 0.0001,using the GENEHUNTER (Cambridge, UK) and VITESSE statisticalprograms for each marker in the genome-wide scan (23,24). Markerallele frequencies were calculated from the unrelated spousesin the family. Map distances for the marker loci were obtainedfrom published data of Marshfield Clinics. Haplotype analysiswas performed by using SIMWALK software and also via visualinspection (25). Two-point and multipoint LOD scores (z scores)and z-1 confidence intervals were calculated on fine mappingdata using VITESSE algorithm as described previously (24,26).A LOD score > 3.0 is considered significant evidence forlinkage, and < -2.0 is significant evidence for exclusionof linkage. A candidate interval was considered excluded whentwo affected individuals within the pedigree inherited differenthaplotypes.
Family Data
CHP Family #177 is a 39-member kindred, with seven affecteds,residing in a well-demarcated geographical area 200 miles northof New Delhi, India. The clinical features of the various familymembers are summarized in Table 1. A total of 18 DNA sampleswere analyzed for the genome-wide scan as shown in Figure 1,and 21 DNA samples were analyzed for fine mapping. None of thefamily members showed any signs of leiomyomatosis, ocular abnormality,altered liver function, macrothrombocytopenia, or polymorphonuclearinclusion bodies. Salient features of some of individuals identifiedby their generation and pedigree ID (GPID) are presented inbrief below.
GPID II:9.
A 38-yr-old male presented with intermittent painless hematuriafor 8 yr and hypertension (BP range, 180 to 120/70 to 104 mmHg)for 2 yr. Urinalysis revealed 4+ proteinuria and RBC > 30to 40/hpf. Investigations showed the following: hemoglobin (Hgb),11 g/dl; white blood cell count (WBC), 9800/mm3; BUN, 22 mg/dl;SCr, 1.0 mg/dl. Audiometry showed high tone deafness.
GPID II:11.
A 35-yr-old male presented with painless hematuria of 12 yrduration. He had developed anasarca 4 yr ago and was found tohave hypertension (BP range, 160 to 120/76 to 100 mmHg) requiringtwo anti-hypertensive drugs (amlodepin 5 mg/d; losartan 25 mgorally twice daily). Investigations showed the following: BUN,63 mg/dl; SCr, 2 mg/dl; phosphorus (P), 6.8 mg/dl; serum albumin(Alb), 3.8 g/dl. A urinalysis showed 3+ to 4+ protein and 30to 40 RBC/hpf. Eye examination did not reveal lenticonus. Audiometryshowed a moderate hearing impairment with a 30 to 40-dB hearingloss at 250 Hz (low tone) and 40 to 50-dB loss at the frequencyof 8000 Hz (high tone). He had normal or near-normal hearingat frequencies ranging from 500 to 4000 Hz (Figure 2). The renaldisease progressed to ESRD with in 1 yr. He underwent a livingrelated renal transplantation, with a sister being the donor,in the year 2000. His current immunosuppression comprises cyclosporine,azathioprine, and prednisolone, and current SCr ranges from1.0 to 1.2 mg/dl. His son (GPID III:9) also shows early stagesof renal involvement manifesting as hematuria and has sensorineuraldeafness. The donor (GPID II:7) was also found to have combinedlow tone (30 to 40 dB) and high tone (40 to 50 dB) sensorineuralhearing loss on audiometry during evaluations for this studybut showed no urinary and renal function anomalies.
Figure 2. Audiogram of GPID II:11 showing unmasked air and bone conduction curves for right and left ears. A mild hearing loss for low frequencies (<1000 Hz) and mild to moderate hearing loss for high frequencies (>4000 Hz) is seen in both ears.
GPID II:13.
A 33-yr-old male presented with painless hematuria and proteinuriaof 8 yr duration with hypertension (BP range, 180 to 110/80to 100 mmHg) for 2 yr, requiring two anti-hypertensive drugs(5 mg/d amlodepin; 5 mg enalapril orally twice daily). Investigationsat presentation revealed the following: urine protein, 2+; RBC,25 to 30/hpf; Hgb, 12.8 g/dl; WBC, 9600/mm3; BUN, 33 mg/dl;SCr, 2.6 mg/dl; Ca, 8.6 mg/dl; P, 4.3 mg/dl; uric acid, 9.4mg/dl; total protein, 5.9 g/dl; Alb, 3.5 g/dl; total bilirubin,0.4 mg/dl; SGOT, 15 IU/L; SGPT, 12 IU/L. The serologic investigationsshowed negative anti-nuclear antibodies and a normal C3. Audiometryshowed high tone sensorineural hearing deficit.
GPID II:15.
A 30-yr-old male presented with intermittent hematuria for 15yr and hypertension (BP range, 150 to 200/76 to 110 mmHg). Heprogressed to ESRD over a period of 6 yr. In March 1997, hisHgb was 5.6 g/dl; WBC, 7000/mm3; BUN, 90 mg/dl; SCr, 5.7 mg/dl.Urinalysis revealed 6 to 8 RBC/hpf and 2+ protein. He receivedliving related renal allograft from his sister (GPID II:3) inAugust 1998. He currently has stable renal function on azathioprineand prednisolone (SCr, 1.5 to 1.7 mg/dl).
Kidney Biopsy Findings
The kidney biopsy was performed in two members, i.e., GPID II:9and II:13, and the findings are shown in Figure 3. The renalhistology was relatively well preserved in GPID II:9 and showedfocal segmental glomerular sclerosis and hyalinosis on lightmicroscopy (Figure 3i, upper panel). The glomerular capillariesappeared to be of normal thickness, and the mesangial cellularitywas not increased. The kidney biopsy in GPID II:13 had inadequatetissue but showed a more advanced disease with focal globalglomerular sclerosis where a number of glomeruli were completelysclerosed (Figure 2ii, upper panel). Blood vessels were unremarkable,but the tubulointerstitial region showed focal tubular atrophywith interstitial fibrosis. The immunofluorescence was negativefor all immunoglobulins and C3 in both GPID II:9 and II:13.Electron microscopic studies on the patient GPID II:9 are shownin the lower panel of Figure 3 (a-f). The most striking featureswere those of variable thickness of the GBM along with areasof rarified membranes. Inflammatory features were absent. GBMthickness, when measured on the thinnest-looking segments, rangedfrom 173.6 to 177 nm (versus normal adult controls thicknessof 350 ± 43 nm [27]). Focal zones of lamellar membraneduplication and irregular thickening were also seen interspersedwith the thin zones. The tubular basement membranes also showedthe same irregular thickening and lamellation as seen in theGBM.
Figure 3. Kidney biopsy findings in CHP family # 177. Upper panel: (i) light microscopic changes in patient II:9 showing a relatively well-preserved cortex with a glomerulus showing segmental sclerosis (arrow); (ii) kidney biopsy in patient II:13 showing a more advanced disease with a partially sclerotic (black arrow) and a completely sclerosed glomerulus (white arrow). Lower Panel: electron microscopic studies of patient II:9. (a) Low-power view showing open capillary loops with normal mesangial and epithelial cellularity; note the thin segments (x8000). (b) Higher-power view showing thicker areas of the GBM (x26000). (c and d) Areas of GBM showing membrane duplication and irregular thickening (c, x19500) and lamellation (d, x26000). (e) Epithelial cell foot process fusion was focal and mild (x34,000). (f) The tubular basement membrane showing lamellation (x26000).
Power Studies and Linkage Analysis
Simulation studies using SLINK showed that the CHP family #177was capable of generating peak LOD scores of 2.4 to 2.8 underan autosomal dominant model, with penetrance ranging from 70to 99%. We first analyzed the genome-wide genotyping data forlinkage to the known candidate genes. This analysis revealednegative LOD scores for chromosome 2q35-q37 region containingCOL4A3 and COL4A4, with marker D2S1363 showing a LOD score of-6.11 and D2S427 showing a LOD score of -2.14 on two-point VITESSEanalysis. Analysis for the markers located at other candidateregions, i.e., for COL4A1 and COL4A2 on chromosome 13q33-q34and MYH9 on chromosome 22q11.2, also revealed consistently negativeLOD scores at = 0 (Table 2). The genomic position for the variousgenes and markers is based on the June 2002 assembly of thehuman genome available through University of California SantaCruz (UCSC) genome browser (http://genome.ucsc.edu). We alsoanalyzed LOD scores for markers near LMX1B, the gene responsiblefor nail-patella syndrome. Although the LOD scores were notless than -2.0, linkage to this region was considered unlikelygiven the negative and low positive LOD scores. We further excludedlinkage to chromosome 1q25 and 19q13 regions, as LOD scoreswere generally less than -2.0 under various penetrance models.The X-linked inheritance was ruled out in view of male-to-maletransmission: i.e., GPID III:19 inherited the disease from GPIDII:11, while GPID III:4 inherited from obligate carrier GPIDII:1 (Figure 1). Also, GPID III:10, although considered unknownfor this study, was found to have low-tone sensorineural deafnessand shares the affected haplotype with his father GPID II:5.
Table 2. Two-point LOD scores for the linked and other candidate regions of FSGS and AS genes
Analysis of genome-wide data by GENEHUNTER under a dominantinheritance model with 80% penetrance identified several chromosomalregions with a LOD score > 1, i.e., chromosomes 11, 3, 13,12, and 15. The chromosome 11–linked region was furtherinvestigated by fine mapping using 13 markers spaced approximately1 to 3 cM apart. The entire FSGS2 interval, spanned by D11S2002to D11S1986, as reported by Winn et al. (6), had LOD scoresless than -2.0. A peak two-point LOD score of 2.02 was obtainedon VITESSE analysis, with 99% penetrance and at = 0 for markerD11S4464 (Table 2). A multipoint LOD score (Z score) of 3.2was obtained for this trait locus, which we denote as FSGSAS,in the same region between markers D11S925 and D11S4464. Figure 4shows the multipoint LOD score and NPL score plots. By usingthe maximum LOD-1 (Z-1) method, we constructed a support intervalwith an asymptotic confidence interval > 95% (26). The FSGSASsupport interval was flanked by maker D11S4460 proximally andD11S1328 distally. The haplotypes for eight of the markers,in the order cen-D11S908, D11S1998, D11S4460, D11S925, D11S4464,D11S1328, D11S934, D11S1304-tel, are shown below each individualgenotyped in Figure 1. Recombinant events in individuals II:11and II:13 also localize the linked region to an approximately7-cM interval bound by markers D11S4460 and D11S1328.
Figure 4. (A) Multipoint LOD (z score) plot for chromosome 11q23–24 region based on VITESSE analyses, and (B) NPL score plot for the same region as generated by GENEHUNTER analyses.
It has become evident that autosomal dominant nephropathy phenotypeincludes many disorders, such as FSGS and AS (2,4,6,7,15,16).Although considerable advances have been made in our understandingof the molecular genetics and pathogenesis of these syndromesover the last decade, new genes and genetic loci continue tobe identified for phenotypes that were once considered to bemonogenic or oligogenic (2,4,9,16). In this report, we presenta family with autosomal dominant progressive nephropathy withfeatures of FSGS and AS including renal failure and deafness.The affected members presented with hypertension, microscopichematuria, and features of nephrotic syndrome. Progressive renalfailure leading to renal transplantation occurred in two membersin the 3rd to 4th decade of life. One of the affected individualspresented with anasarca, while another presented with a lessprogressive renal disease manifesting with nephrotic range proteinuria,but without the full-blown nephrotic syndrome. Affected membersalso had sensorineural deafness but no eye or hematologic abnormalities.This family did not show linkage to currently identified lociassociated with either the AS phenotype (i.e., COL4 genes) orEpstein/Fechtner syndrome (MYH9). Linkage of this trait wasalso excluded for the chromosomal regions that are linked withFSGS phenotype, i.e., the FSGS2 region on 11q21 reported byWinn et al.; chromosome 1q25 (podocin [NPHS2] gene); and 19q13(nephrin [NPHS1] and alpha actinin-4 [ACTN4] genes) (6–9).Our findings suggest that this is a new syndrome associatedwith ESRD and linked to a new region on chromosome 11q24.
We chose a rather conservative approach for the affected statusclassification scheme to minimize the possibility of misclassification.Indeed, many of the individuals classified as unknown had haplotypesthat segregated with the disease allele and had abnormalitiesdetected on audiometry or urinalyses. If these individuals wereto be considered as affecteds, the LOD scores increase significantly.Also, the disease appeared to be more severe in males, and male-to-maletransmission was seen. Another interesting point is that ofunaffected obligate heterozygote (GPID II:1), suggesting incompletepenetrance. This highlights the difficulty in assigning accuratepenetrance parameters for this disorder. It thus appears thatindividuals with this trait can have the disease gene and becompletely asymptomatic even if they are much older than theaverage age of onset.
The current family showed considerable phenotypic heterogeneitywith respect to age of onset, association of renal and hearinganomalies, and penetrance. These features are also seen in AS,where renal disease generally manifests as recurrent microscopicor gross hematuria associated with high frequency sensorineuralhearing loss and/or ocular anomalies and progression to renalfailure usually occurs, at least in males, by the fifth decade(5). The classic AS phenotype, however, shows considerable phenotypicheterogeneity in the age of onset of ESRD, and the severityof auditory and renal features may not correlate (11,28). Therenal histology in AS can also be variable and involves bothglomerular and tubulointerstitial abnormalities. The ultrastructuralchanges of irregularly thickened and attenuated GBM, as wellas the "basket weave" alteration in the lamina densa, have beenconsidered to be a pathognomonic histologic feature of AS (28).A kidney biopsy was performed in two individuals in our reportand showed glomeruli with features of FSGS on light microscopyand negative immunofluorescence along with significant tubulointerstitialdisease. The electron microscopy showed varying GBM thicknessincluding some very thin areas. A "basket weave" pattern wasalso seen in the tubular basement membrane, although this featureis not specific to AS. These histologic findings thus comprisefeatures of both FSGS and AS.
The classic phenotype of AS generally segregates as an X-linkeddominant disorder and is associated with mutations in the COL4A5gene (12). In addition to the X-linked forms, both autosomalrecessive and dominant forms have been described. Recent identificationof mutations in COL4A3 and COL4A4 genes, which are located intandem on 2q35-q37 (13–16) in both autosomal recessiveand dominant forms suggest that AS phenotype is a disorder thatis mostly associated with COL4 genes (28,29). In the presentreport, we excluded linkage to all of these collagen genes aswell as to COL4A1 and COL4A2 region on chromosome 13, whichis not yet associated with any human disease. A unique characteristicof this syndrome may be that the affecteds have features ofboth low-tone and high-tone deafness. A review of literaturerevealed a possibly similar familial nephropathy reported byMotoyama et al. in Japan (30). The proband in that family wasa 14-yr-old girl with hematuria and proteinuria that was alsoseen in several affecteds on the maternal side of the pedigree.She developed nephrotic syndrome with mild renal dysfunction(creatinine clearance, 57.9 ml/min per 1.48 m2) and a renalbiopsy showed segmental mesangial hypercellularity, numerousinterstitial foam cells, and thinning and splitting of the GBM.Audiologic studies detected bilateral low-tone (from 125 Hzto 1000 Hz) sensorineural hearing difficulty, ranging from 30to 40 dB. Audiogram of her brother also revealed low-tone sensorineuralhearing loss. Their mother had nephrotic syndrome during pregnancy,and her renal biopsy had shown mild mesangial proliferationwith irregularity of GBM. Further identification of such casesand similar pedigrees may define this syndrome further.
Besides classic AS, it has lately become evident that some casesmanifesting with dominant hereditary nephropathy and deafnessmay have hematologic abnormalities and would then actually beconsidered to have Epstein syndrome (MIM 153650), or Fechtnersyndrome (MIM 153640) (28). Some families with Fechtner syndromehave also been reported with cataracts or altered liver function(31). These megakaryocytic syndromes are now considered allelicand are associated with mutations in the gene encoding nonmusclemyosin heavy chain IIA (MYH9), located on chromosome region22q11-q13 (18). The family that we report had no identifiableplatelet or neutrophil anomalies, and the affecteds had normalliver function. We excluded linkage to chromosome region 22q11-q13region in this family. We also studied linkage to chromosome9 markers for another autosomal dominant nephropathy, i.e.,nail-patella syndrome, which is associated with mutations inLMX1B, although the reported family did not have many of thefeatures of this syndrome (3). Our results showed that suchlinkage was unlikely and the locus identified by us most likelyrepresents association with a new syndrome.
In addition to the AS phenotype, some of the affecteds in thisreport had features of nephrotic syndrome, which is commonlyseen with FSGS but is infrequently noted in AS (32). The pathogenesisof FSGS is only partially understood, although genetic factorshave been increasingly thought to play a major role (2,4). Recentstudies have implicated mutations in ACTN4 (on chromosome 19q13)and linkage to chromosome 11q21–22 region (FSGS2 locus)in the pathogenesis of dominantly inherited FSGS (6,7). Thegene for FSGS2 is currently unknown. However, most of the autosomaldominant FSGS cases do not map to 19q13 or 11q21–22 orhave not been found to have mutations in ACTN4 (4,6). Theseobservations suggest that FSGS may be a final common pathwayof several forms of glomerular injury and possibly several othergenes remain to be discovered. Our findings localized the FSGSAStrait in CHP 177 family to approximately 7-cM region on chromosome11q24, and linkage was excluded for the entire FSGS2 intervalspanned by D11S2002–D11S1986 reported by Winn et al. (6).The histologic heterogeneity seen in our reported family isconsistent with monogenic renal disease and has also been reportedbefore by several groups, including our group and also by Winnet al. and Mathis et al. (6,7,24). The linked area on chromosome11q24 in this family is approximately 20 cM telomeric to FSGS2locus and has several interesting candidate genes. One suchgene, tectorin alpha (TECTA), shares homology with utrophinand is mutated in a dominant form of inherited deafness (33).Utrophin is a paralogue of dystrophin and has two full-lengthmRNA species, A and B, which have very different expressionpatterns. B-utrophin is expressed in vascular endothelial cells,whereas A-utrophin is expressed at the neuromuscular junction,choroid plexus, pia mater, and renal glomerulus (34). TECTAis not expressed in the kidneys, but computer modeling predictspresence of several tectorin-like genes in this region thatwould need to be studied further. Another strong candidate genein this region could be CDON, named after a surface glycoproteinthat transcribes a cell adhesion molecule-related protein, whichis downregulated by oncogenes (35). It is a member of the Igsuperfamily and may have functional similarity to nephrin, whichis mutated in the autosomal recessive congenital nephrotic syndromeof Finnish type (9). Studies are currently in progress to narrowthe region further and to analyze the sequence of these twogenes in the affecteds.
In summary, our findings suggest further locus heterogeneityfor autosomal dominant nephropathy phenotype. Most of the autosomaldominant nephropathies with features of nephrotic syndrome donot, as yet, have an identifiable genetic cause; it is thereforehoped that our findings would contribute to search for additionalloci for this phenotype. Identification of new families withlinkage to 11q24 locus will aid in localization of causativegene and would help in our understanding of the pathophysiologyof disorders associated with ESRD.
Acknowledgments
This study was supported by a Young Investigator award fromthe National Kidney Foundation and NIH (K23-DK02854) to AbhayVats. We thank the NHLBI mammalian genotyping service at MarshfieldClinics for performing the genome-wide scans on this familyas a part of a larger project. We also would like to thank audiologistClyde G. Smith, MS, for help with the interpretation of theaudiometry data and Janet Walpusk for assistance with electronmicroscopy. We are grateful to the reported family members fortheir participation. The paper was partially presented in abstractform at the Annual Society of Nephrology meeting held in PhiladelphiaPA, in November 2002. Dr Abhay Vats is a consultant for ViraCorBiotechnologies.
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Abstract
Introduction
= 0. The z-1 confidence interval for the linked region spans a genetic distance of 7 cM. This study thus reports an autosomal dominant nephropathy with features of both FSGS and AS in which linkage to currently known loci for such phenotypes was excluded and a new locus on 11q24 was identified. The findings suggest further locus heterogeneity for the autosomal dominant nephropathy phenotype. E-mail: abhay.vats@chp.edu 
) and unaffected females (
). The filled symbols represent affected males (
) and affected females (•). The 
