Confirmation of the ATP6B1 gene as responsible for distal renal tubular acidosis.

Primary distal renal tubular acidosis (dRTA) type I is a hereditary renal tubular disorder, which is characterized by impaired renal acid secretion resulting in metabolic acidosis. Clinical symptoms are nephrocalcinosis, nephrolithiasis, osteomalacia, and growth retardation. Biochemical alterations consist of hyperchloremic metabolic acidosis, hypokalemia with muscle weakness, hypercalciuria, and inappropriately raised urinary pH. Autosomal dominant and rare forms of recessive dRTA are known to be caused by mutations in the gene for the anion exchanger AE1. In order to identify a gene responsible for recessive dRTA, we performed a total genome scan with 303 polymorphic microsatellite markers in six consanguineous families with recessive dRTA from Turkey. In four of these there was an association with sensorineural deafness. The total genome scan yielded regions of homozygosity by descent in all six families on chromosomes 1, 2, and 10 as positional candidate region. In one of these regions the gene ATP6B1for the ss1 subunit of the vacuolar H(+)-ATPase is localized, which has recently been identified as causative for recessive dRTA with sensorineural deafness. Therefore, we conducted mutational analysis in 15 families and identified potential loss-of-function mutations in ATP6B1in 8. We thus confirmed that defects in this gene are responsible for recessive dRTA with sensorineural deafness.

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.