Identification of a Gene Locus for Senior-Løken Syndrome in the Region of the Nephronophthisis Type 3 Gene
Heymut Omran*,
GÜrsel Sasmaz*,
Karsten Häffner*,
Andreas Volz*,
Heike Olbrich*,
Rachid Melkaoui*,
Edgar Otto*,
Thomas F. Wienker,
Rudolf Korinthenberg*,
Matthias Brandis*,
Corinne Antignac and
Friedhelm Hildebrandt*
*University Children’s Hospital Freiburg and Institute for Medical Biometry, Informatics and Epidemology, University of Bonn, Bonn, Germany; Inserm U423, Hôpital Necker-Enfants Malades, Paris, France
Correspondence to Dr. Heymut Omran, University Children’s Hospital, Mathildenstrasse 1, 79106 Freiburg, Germany. Phone: 49-761-270-4301; Fax: 49-761-270-4533; E-mail: omran{at}kkl200.ukl.uni-freiburg.de
ABSTRACT. Senior-Løken syndrome is an autosomal recessivedisease with the main features of nephronophthisis (NPH) andLeber congenital amaurosis. The gene for adolescent nephronophthisis(NPHP3) was recently localized to chromosome 3q21-q22. The hypothesiswas tested that Senior-Løken syndrome (SLS) might localizeto the same region by studying a kindred of German ancestrywith extended consanguinity and typical findings of SLS. Twentyhighly polymorphic markers located in the vicinity of the NPHP3genetic region were tested. Haplotype analysis revealed homozygosityby descent in affected individuals, and linkage analysis yieldeda parametric maximum multipoint logarithm of likelihood of odds(LOD) score of 3.14, thus identifying the first locus for SLS.The SLS1 locus is flanked by D3S1587 and D3S621 and containsa 14-cM interval that contains the whole critical NPHP3 region.Three additional families with SLS were studied, and evidencefor genetic heterogeneity in one of them was found. Localizationof a SLS locus to the region of NPHP3 opens the possibilitiesof both diseases arising by mutations within the same pleiotropicgene or two adjacent genes.
Nephronophthisis (NPH) is an autosomal recessive cystic kidneydisease that causes progressive renal failure (1). A gene forjuvenile NPH (NPH1, MIM 256100) was localized on chromosome2q12-q13 (2,3). The responsible gene (NPHP1) has recently beenidentified (4,5). For infantile NPH (NPH2, MIM 602088), a locuswas mapped to chromosome 9q22-q31 (6). We recently identifieda novel type of NPH that leads to end-stage renal disease ata median age of 19 yr (7), adolescent NPH (NPH3, MIM 604387),in a large Venezuelan kindred. With the use of a homozygositymapping strategy, the responsible gene (NPHP3) was localizedon human chromosome 3q21-q22, which is homologous to the murinerenal cystic disease locus pcy on mouse chromosome 9 (8). Clinicalsigns of NPH3 consist of renal symptoms such as polyuria, polydipsia,secondary enuresis, severe anemia, and progressive renal failure.Renal pathology is characterized by cysts at the corticomedullaryjunction. Renal histology shows the characteristic triad ofirregularly thickened tubular basement membranes, atrophy anddilatation of tubules, and sclerosing tubulointerstitial nephropathy.However, histology is not pathognomonic for NPH3, and diagnosisrelies on typical clinical history, sonographic findings, andexclusion of other renal diseases (7). NPH has been associatedwith several extrarenal associations such as Leber congenitalamaurosis (LCA), cerebellar ataxia, skeletal involvement, congenitaloculomotor apraxia, and hepatic fibrosis (9–13). The term"Senior-Løken syndrome" (SLS) denotes the associationof NPH and LCA (MIM 266900). LCA (MIM 204000/204100) is a clinicallyand genetically heterogeneous retinal disorder that occurs ininfancy and is accompanied by profound visual loss, nystagmus,poor pupillary reflexes, and either a normal retina or varyingdegrees of atrophy and pigmentary changes (14–16). Theelectroretinogram is extinguished or severely reduced (17).LCA is inherited as an autosomal recessive trait. To date, fourgenes for LCA have been identified: retinal guanylate cyclase(RETGC1) on chromosome 17p13 (18,19), retinal pigment epitheliumprotein (RPE65) on chromosome 1p31 (20,21), cone-rod homeobox(CRX) on chromosome 19q13.3 (22), and aryl hydrocarbon receptor–interactingprotein-like 1 (AILP1) on chromosome 17p13 (23). Two additionalloci for LCA have been reported on chromosomes 14q24 and 6q11-q16(24,25). In this study, we pursued a focused approach directedat the NPH3 gene locus; we tested a consanguineous family ofGerman ancestry with SLS for linkage to the NPHP3 region onchromosome 3q21-q22. Extensive pedigree analysis detected multipleconsanguineous loops with a remote degree of consanguinity datingback to the 17th century. Because this remote consanguinitycontrols for many meioses, identification of homozygosity bydescent in the two affected individuals allowed localizationof a novel gene locus for SLS. Thus the NPHP3 locus harborsa gene or genes responsible for SLS in this family. By studyingother families with SLS, we demonstrated genetic heterogeneity.
Patients
Five members of a German family originating from northern Germanywith SLS were investigated (Figure 1). The two affected siblingsof this family had nearly identical clinical and diagnosticfindings; therefore, the clinical description is pertinent toboth. In infancy, pressing on the globes (the digito-ocularphenomena of Franceschetti-Bamatter) played a prominent partin childhood behavior and brought them to medical attention.On ophthalmologic investigations, they had poor visual acuitiesin the order of 0.05 to 0.1 (normal value 1.0), nystagmus, poorpupillary reflexes, retinal mottling, and high hypermetropia.The electroretinogram was abolished. Later, when visual fieldtesting became possible, they had severe tubelike restrictionof the visual fields. Both affected siblings developed renalsymptoms such as polyuria, polydipsia, secondary nocturnal enuresis,and progressive renal failure. For the creatinine course, see(Figure 2). Renal replacement therapy had to be implementedat the age of 15 and 12 yr, respectively. Only minor proteinuriaof 0.4 g (0.6 g)/24 h was noted. On renal sonography, the kidneysappeared to be of normal to slightly reduced size, with cystsat the corticomedullary junction and increased echogenicity.No urinary tract abnormality was observed. After demonstrationof linkage of SLS in F1, three additional families with SLSwere studied. In all families, diagnosis of SLS was based on(1) pedigree structure suggestive for autosomal recessive inheritance;(2) profound visual loss, nystagmus, poor pupillary reflexes,and varying degrees of atrophy and pigmentary changes of theretina; (3) abolished electroretinogram; (4) renal symptomstypical for NPH: polyuria, polydipsia, secondary nocturnal enuresis,and progressive renal failure; (5) sonography of the kidneyscharacteristic of NPH with cysts at the corticomedullary junctionor renal biopsy compatible with the diagnosis of NPH3; and (6)absence of other renal disease.
Figure 1. Pedigree of the consanguineous German family F1 with Senior-Løken syndrome (SLS). Haplotypes for markers on chromosome 3q21-q22 are shown from centromeric to telomeric (top to bottom) direction. Flanking markers D3S1587 and D3S621 of the SLS locus are underlined. Flanking markers of the NPHP3 region D3S1292 and D3S1238 are indicated by arrows. Solid symbols denote affected individuals; open symbols denote unaffected individuals. Double horizontal lines between parents indicate consanguinity. Microsatellite marker loci are given in the first column. The haplotype segregating with the disease locus is indicated by a black bar. The year of birth is given below the symbol for each individual.
Figure 2. Creatinine course for the two affected individuals of the German family with SLS (see (Figure 1)). The dotted line represents the serum creatinine course of the affected girl and the other that of her affected brother.
Genetic Study
Venous blood samples from family members were obtained afterinformed consent was obtained. DNA was prepared according tostandard methods. The NPHP1 locus for juvenile NPH on chromosome2q12-q13 was excluded by haplotype analysis (data not shown).Infantile NPH was excluded by clinical means, because end-stagerenal disease was reached after age 3 yr. Haplotype analysiswas performed as described elsewhere, by use of highly polymorphicmicrosatellites residing at the NPHP3 locus on chromosome 3q21-q22(7). Marker order was based on physical mapping data of theNPHP3 region that have been reported elsewhere (8) and informationavailable at the Weizman Institute for Bioinformatics (URL givenbelow). Parametric two-point and multipoint analysis in familyF1 was performed by use of the program ALLEGRO (26). SLS wasanalyzed as an autosomal recessive trait with complete penetranceand an assumed gene frequency of 0.003, for a conservative estimate.Likewise, only the smallest consanguinity loop for the logarithmof likelihood of odds (LOD) score calculation was used, whichresulted in a probably slight underestimation of the maximumLOD score. A total of 20 microsatellite markers were analyzed.Allele frequencies of markers were arbitrarily assigned a valueof 1/n, where n refers to the number of alleles at each marker.Numbers of alleles were taken from Dib et al. 1996 (27). Recombinationfrequencies for males and females were assumed to be equal.The ALLEGRO program was used to perform parametric multipointlinkage analysis against a fixed map of 20 markers by use ofthe genetic model detailed above (26). Usually, incorrect parametersof the genetic model in linkage analysis does not affect thetype I error rate, i.e., will not result in false-positive resultsbut rather in loss of statistical power. This is quite differentin homozygosity mapping when marker allele frequencies are concerned.Too low an estimate of the cosegregating marker allele frequencieseventually will lead to a false-positive result. Therefore,as a test for robustness, multipoint LOD scores were recalculatedin a second model that used marker allele frequencies of 1/n,where n refers to the observed number of alleles in the examinedfamily, which resulted in allele frequencies ranging from 0.3333to 0.500 for informative markers.
Haplotype studies of the German kindred F1 showed a result compatiblewith homozygosity by descent in all affected individuals, coveringthe whole NPHP3 region (Figure 1). Recombinants observed forD3S1587 and D3S621 defined the critical disease interval, whichspans a 14-cM interval. Parametric LOD score calculation achieveda maximum two-point LOD score of Zmax = 1.06 ( = 0) for markerD3S3637. Multipoint LOD score calculation resulted in a significantparametric LOD score (Zmax = 3.14) in the interval between markersD3S3548 and D3S1309. For detailed results, see (Table 1). Whenhigher allele frequencies were used as a test of robustness,the maximum multipoint LOD score remained stable (Zmax = 3.13).
Table 1. Multipoint likelihood of odds score results for family F1 between the SLS1 locus and markers from the NPHP3 region on chromosome 3q21-q22a
Haplotype analysis of three additional families tested for thenewly identified SLS region are shown in (Figure 3). One family(F353) showed a haplotype analysis compatible with homozygosityby descent in the affected individual, which is consistent withlinkage. Haplotype analysis of family F15 excluded linkage tothe examined region, because both affected individuals do notshare the same haplotype, thus giving evidence for further geneticheterogeneity in SLS. In family F335, both affected childrenshare the same haplotypes, but no homozygosity by descent wasobserved, which is highly suggestive of absence of linkage inthis consanguineous family.
Figure 3. Pedigrees of three additional families with SLS. Haplotypes for markers on chromosome 3q21-q22 are shown from centromeric to telomeric (top to bottom) direction. Flanking markers D3S1587 and D3S621 of the SLS locus are underlined. Solid symbols denote affected individuals; open symbols denote unaffected individuals. Double horizontal lines between parents indicate consanguinity. Microsatellite marker loci are given in the first column. The haplotype segregating with the disease locus is indicated by a black bar. Note that the haplotype analysis of family F353 is compatible with linkage and indicative for homozygosity of descent. Haplotype analysis of family F15 excludes linkage to the examined region.
Testing a candidate locus hypothesis, we were able to demonstratethat a gene locus for SLS (SLS1) maps on chromosome 3q21-q22within a 14-cM interval flanked by D3S1587 and D3S621, whichcontains the whole critical region of NPHP3 (Figure 1). Ourstudies provide several lines of evidence for the localizationof the first gene locus for SLS. First, parametric LOD-scorecalculation achieved a significant multipoint LOD score, andmultipoint LOD scores remained robust toward the change of allelefrequencies. Second, both affected siblings of the family showedidentical haplotypes compatible with homozygosity by descent(Figure 1). This is an expected finding in individuals froman inbred population affected by rare autosomal recessivelytransmitted diseases who inherit identical alleles from a commonancestor. The chromosomal segment of homozygosity by descent—thatis, shared by affected relatives—is likely to harbor theresponsible gene for the disease because of the rarity of diseasealleles in the population (28). Third, by use of a focused approach,the multiple testing problem as it occurs in a total genomescan was avoided, thus minimizing the risk of finding homozygosityby descent by chance (29). Fourth, we found linkage in a candidateregion where a gene responsible for NPH is located, which isa key feature of SLS. Haplotype studies of other families withSLS identified a consanguineous family (F353) with a haplotypeanalysis compatible with homozygosity by descent and linkageto the examined region. If linkage in this family is not spurious,the region of interest would be restricted telomeric to D3S1273(Figure 3).
Three potential genetic mechanisms may serve to explain thefinding of linkage of SLS to the NPHP3 locus. (1) A pleiotropiceffect caused by different mutations within a single gene maybe responsible for the association of LCA and NPH3. (2) Twogenes might be located in close vicinity to each other in theNPHP3 region, which are independently responsible for LCA andNPH3. In this model, SLS would be a result of a contiguous genedeletion syndrome involving both genes (30). (3) Two adjacentgenes independently cause SLS and NPH3, and localization ofthe SLS locus occurred only by chance in vicinity of the NPHP3region. The latter possibility is the least likely. By haplotypeanalysis that used a dense set of polymorphic markers, we havenot obtained evidence for a deletion yet. Cloning the NPHP3region identified seven expressed genes (ACPP [acid phosphatase,prostate-specific], TOPB1 [topoisomerase (DNA) II binding protein],EDF1 [endothelial differentiation-related factor 1], TF [transferrin],DGKZ [diacylglycerol kinase-zeta], SLC21a2 [prostaglandin transporter,PGT], and RYK [receptor-like tyrosine kinase]) and eight expressed-sequencetags, most with unknown function (8). On the basis of availablefunctional information for these genes, there is no clear candidatefor NPH or LCA. The identification of the first SLS locus hopefullywill aid gene identification in NPH3, because the search forpotential candidate genes can be based on hypotheses for LCAand NPH3.
The differentiation between LCA with isolated involvement ofthe eye and SLS has important clinical implications, becausepatients with LCA without genetic evidence for isolated LCA(LCA types 1 to 6) should have regular measurement of renalfunction parameters. Otherwise, in these patients, developmentof chronic renal failure eventually might be missed, and residualvisual function may be impaired by hypertension or uremia. Itis important to know that renal function may remain normal fora long time, and some patients with SLS develop renal failurein adulthood (31–33). A study that examined several familieswith SLS excluded linkage to the NPHP1 locus (2). After genetictesting of NPHP1 became available, three families with homozygousdeletions of NPHP1 and mild to moderate late-onset tapetoretinaldegeneration were reported (34). However, these patients didnot meet the diagnostic criteria of LCA. Patients developedonly minor visual impairment and therefore do not representclassical SLS. Recently, we found evidence for further geneticheterogeneity in isolated NPH (35). In this study, we give evidencealso for further genetic heterogeneity in SLS, because haplotypeanalysis of family F15 excluded linkage to the examined markers.Obviously, clinical as well as genetic heterogeneity is a prominentfeature of the NPH syndromes.
In summary, a candidate locus study and homozygosity mappingstrategy has identified the first locus for SLS, which is identicalwith the NPHP3 locus on chromosome 3q21-q22. Mapping of thisSLS locus and subsequent gene identification will aid the understandingof molecular mechanisms that cause Leber congenital amaurosisand adolescent nephronophthisis.
Acknowledgments
We are indebted to the families who participated in this study.The authors would also like to thank Dr. M. Bulla (Münster)and Dr. R. Burghard (Memmingen) for clinical information onaffected individuals. H.O. and F.H. were supported by a grantfrom the German Research Foundation (DFG Om 6/1 to 2, DFG Om6/2 to 1 and DFG Hi 381/3 to 3) and by a grant from the ZentrumKlinische Forschung, Freiburg (ZKF-A1).
Footnotes
Electronic-Database information: Online Mendelian Inheritancein Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim (for LCA [MIM204000/204100];NPH1 [MIM 256100]; NPH2 [MIM 602088]; NPH3 [MIM 604387]; SLS[MIM 266900]). Weizman Institute for Bioinformatics, http://bioinformatics.weizman.ac.il/UDB
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Received for publication April 16, 2001.
Accepted for publication August 27, 2001.
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Abstract
Introduction
= 0) for marker D3S3637. Multipoint LOD score calculation resulted in a significant parametric LOD score (Zmax = 3.14) in the interval between markers D3S3548 and D3S1309. For detailed results, see (Table 1). When higher allele frequencies were used as a test of robustness, the maximum multipoint LOD score remained stable (Zmax = 3.13). 
