Mapping a new suggestive gene locus for autosomal dominant nephrolithiasis to chromosome 9q33.2–q34.2 by total genome search for linkage

Background. Nephrolithiasis is a complex, multifactorial disease resulting from genetic and environmental interaction. The pathogenesis of nephrolithiasis is far from being understood. So far, no gene locus for autosomal dominant nephrolithiasis only has been described. We here identified a new suggestive gene locus for autosomal dominant nephrolithiasis by a genome-wide search for linkage in a Spanish kindred with nephrolithiasis. Methods. Clinical data, blood and urine samples of 18 individuals from a Spanish kindred with nephrolithiasis were collected. We performed a genome-wide search for linkage using 380 polymorphic microsatellite markers. Results. Nephrolithiasis segregated in this Spanish kindred in a pattern compatible with autosomal dominant inheritance. The total genome search yielded the highest two-point LOD score of Z max = 1.99 (θ = 0) for marker D9S159 on chromosome 9q33.2-q34.2. Multipoint analysis of 24 polymorphic markers used for further fine mapping resulted in a LOD score of Z max = 2.7 (θ=0) for markers D9S1881-D9S164, thereby identifiying a new gene locus for autosomal dominant nephrolithiasis (NPL1). Two recombination events define D9S1850 as the centromeric flanking marker and D9S1818 as the telomeric flanking marker, restricting the NPL1 locus to a 14Mb interval. Conclusion. We here identified a new suggestive gene locus (NPL1) for autosomal dominant nephrolithiasis. It is localized on chromosome 9q33.2-q34.2. The identification of the responsible gene will provide new insights into the molecular basis of nephrolithiasis.