Mapping of gene loci for nephronophthisis type 4 and Senior-Løken syndrome, to chromosome 1p36.
For nephronophthisis (NPHP), the primary genetic cause of chronic renal failure in young adults, three loci have been mapped. To identify a new locus for NPHP, we here report on total-genome linkage analysis in seven families with NPHP, in whom we had excluded linkage to all three known NPHP loci. LOD scores >1 were obtained at nine loci, which were then fine mapped at 1-cM intervals. Extensive total-genome haplotype analysis revealed homozygosity in one family, in the region of the PCLN1 gene. Subsequent mutational analysis in this gene revealed PCLN1 mutations, thereby allowing exclusion of this family as a phenocopy. Multipoint linkage analysis for the remaining six families with NPHP together yielded a maximum LOD score (Z(max)) of 8.9 (at D1S253). We thus identified a new locus, NPHP4, for nephronophthisis. Markers D1S2660 and D1S2642 are flanking NPHP4 at a 2.9-cM critical interval. In one family with NPHP4, extensive genealogical studies were conducted, revealing consanguinity during the 17th century. On the basis of haplotype sharing by descent, we obtained a multipoint Z(max) of 5.8 for D1S253 in this kindred alone. In addition, we were able to localize to the NPHP4 locus a new locus for Senior-Løken syndrome, an NPHP variant associated with retinitis pigmentosa.
Schuermann
Maria J
MJ
University Children's Hospital, Freiburg University, Freiburg, Germany.
Otto
Edgar
E
Becker
Achim
A
Saar
Katrin
K
Rüschendorf
Franz
F
Polak
Bettine C
BC
Ala-Mello
Sirpa
S
Hoefele
Julia
J
Wiedensohler
Alexander
A
Haller
Maria
M
Omran
Heymut
H
Nürnberg
Peter
P
Hildebrandt
Friedhelm
F
D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D003241:Consanguinity; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000235:genetics*; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000150:complications* / Q000235:genetics*; D012984:Software; D013577:Syndrome
D005819:Genetic Markers