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Mapping of gene loci for nephronophthisis type 4 and Senior-Loken syndrome, to chromosome 1p36

Official URL:https://doi.org/10.1086/340317
PubMed:View item in PubMed
Creators Name:Schuermann, M.J. and Otto, E. and Becker, A. and Saar, K. and Rueschendorf, F. and Polak, B.C. and Ala-Mello, S. and Hoefele, J. and Wiedensohler, A. and Haller, M. and Omran, H. and Nuernberg, P. and Hildebrandt, F.
Journal Title:American Journal of Human Genetics
Journal Abbreviation:Am J Hum Genet
Volume:70
Number:5
Page Range:1240-1246
Date:May 2002
Keywords:Chromosome Mapping, Chronic Kidney Failure, Consanguinity, Genetic Markers, Haplotypes, Homozygote, Human Pair 1 Chromosomes, Lod Score, Microsatellite Repeats, Pedigree, Retinitis Pigmentosa, Software, Syndrome
Abstract: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-Loken syndrome, an NPHP variant associated with retinitis pigmentosa.
ISSN:0002-9297
Publisher:University of Chicago Press (U.S.A.)
Item Type:Article

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