Localization of a gene for nonsyndromic renal hypodysplasia to chromosome 1p32-33

Abstract

Nonsyndromic defects in the urinary tract are the most common cause of end-stage renal failure in children and account for a significant proportion of adult nephropathy. The genetic basis of these disorders is not fully understood. We studied seven multiplex kindreds ascertained via an index case with a nonsyndromic solitary kidney or renal hypodysplasia. Systematic ultrasonographic screening revealed that many family members harbor malformations, such as solitary kidneys, hypodysplasia, or ureteric abnormalities (in a total of 29 affected individuals). A genomewide scan identified significant linkage to a 6.9-Mb segment on chromosome 1p32-33 under an autosomal dominant model with reduced penetrance (peak LOD score 3.5 at D1S2652 in the largest kindred). Altogether, three of the seven families showed positive LOD scores at this interval, demonstrating heterogeneity of the trait (peak HLOD 3.9, with 45% of families linked). The chromosome 1p32-33 interval contains 52 transcription units, and at least 23 of these are expressed at stage E12.5 in the murine ureteric bud and/or metanephric mesenchyme. These data show that autosomal dominant nonsyndromic renal hypodysplasia and associated urinary tract malformations are genetically heterogeneous and identify a locus for this common cause of human kidney failure.

Figure 1.

Pedigree structure of the seven families studied. Patients with childhood end-stage renal disease (ESRD) but no sonographic data available are indicated by a blackened rectangle inside the symbol. Arrows identify the index cases. Asterisks (*) mark the individuals from whom DNA was available for the study. Individual identification numbers correspond to table 1.

Figure 2.

LOD score distribution across the genome. The continuous lines (A) represent the HLOD scores obtained from the SNP scan with affected-only analysis of all seven pedigrees (minimum HLOD=0). The dashed lines (B) represent the parametric LOD scores obtained from microsatellite scan in pedigree K100 alone. Values <−6 are not shown. Chr = chromosome.

Figure 3.

LOD plot of chromosome 1p32-33 locus. The multipoint LOD score in K100 and the HLOD in all seven pedigrees combined are shown. The X-axis shows genetic distance based on the deCODE map. The location of microsatellite markers genotyped is shown above the graph. The LOD-1 support interval is indicated by the thick horizontal bar above the LOD curve.

Figure 4.

Haplotype structure of the three pedigrees that show linkage to the 1p32-33 locus. Genotypes for the most informative markers spanning the linkage interval are shown (19 of 51 SNPs and microsatellite loci genotyped are shown). The vertical bars highlight the linked (black) and the wild-type (white) haplotypes. The physical locations of the markers are indicated in a list at the top right. Patients with childhood end-stage renal disease (ESRD) but no sonographic data available are indicated by a blackened rectangle inside the symbol.