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

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-Løken syndrome, an NPHP variant associated with retinitis pigmentosa.

Figure 1

Haplotypes on chromosome 1p36 in six families with NPHP4. Eleven microsatellites, from p-ter to cen (top to bottom), are shown to the left of the pedigrees. Circles denote females; squares denote males; filled symbols indicate affected status. Haplotypes are indicated by as differently shaded bars. In family F30, the double line indicates consanguinity, and genotypes homozygous by descent in affected individuals are boxed. Markers flanking the NPHP4 locus, as defined by lack of homozygosity in family F30, are underlined.

Figure 2

Multipoint LOD scores for the NPHP4 locus, versus the 11 markers shown in figure 1, calculated in all six families with NPHP4. Positions (in cM) are according to the Généthon map relative to the position of D1S243 (Dib et al. 1996). The two markers—D1S2660 and D1S2642—that flank the NPHP4 region (see fig. 1) are underlined. p-ter = p-terminal orientation; cen = centromeric orientation.

Figure 3

Discovery of consanguinity in family F30. Year of birth is indicated below the symbol for each individual (but, in the last two generations, is omitted, to ensure anonymity). Note that consanguinity in the 17th century was detected; tracing of the consanguinity loop was facilitated by the occurrence of a rare name (“R”) and residence in a small township (“e”). Symbols are as in figure 1. A slash through a symbol indicates that the individual is deceased.

Figure 4

Haplotypes on chromosome 1p36.31 of family F3 with SLS. Eight microsatellite markers, from p-ter to cen (top to bottom), are shown to the left of the pedigrees. Symbols are as in figure 1. In each of the affected individuals, the genotypes homozygous by descent are boxed. The two markers—D1S468 and D1S436—that flank the SLSN4 region are underlined.