Mapping the gene causing X-linked recessive nephrolithiasis to Xp11.22 by linkage studies.

Abstract

X-linked recessive nephrolithiasis is associated with kidney stones and renal tubular dysfunction in childhood progressing to renal failure in adulthood. The primary defect causing this renal tubular disorder is unknown and determining the chromosomal location of the mutant gene would represent an important step toward defining the biochemical basis. We have performed linkage studies in 102 members (10 affected males, 47 unaffected males, 15 obligate heterozygote females, and 30 unaffected females) from five generations of one family. As genetic markers we used 10 cloned human X chromosome fragments identifying restriction fragment length polymorphisms and seven pairs of oligonucleotide primers identifying microsatellite polymorphisms. Linkage with the locus DXS255 was established with a peak LOD score = 5.91 at 3.6% recombination, thereby localizing the X-linked recessive nephrolithiasis gene to the pericentromeric region of the short arm of the X chromosome (Xpl 1.22). Multilocus analysis indicated that the mutant gene was distal to DXS255 but proximal to the Duchenne muscular dystrophy locus on Xp. Thus, the gene that causes X-linked recessive nephrolithiasis maps to the pericentromeric region of the short arm of the X chromosome (Xpll.22), and further characterization of this gene will help to elucidate the factors controlling renal tubular function and mineral homeostasis. (J. Clin. Invest. 1993Invest. . 91:2351Invest. -2357

Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism.

“…2). Restriction fragment length polymorphisms and microsatellite polymorphisms were detected using previously described methods (23)(24)(25)(26) were designed to amplify exons 2 to 7, and 9 of the 12 intron/exon boundaries; the 7 novel primers are indicated in bold and the DNA sequences of the remaining 17 primers have been reported previously (3). Corp., Cleveland, OH) protocol was performed as described previously (27).…”

Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5).

“…Thus, XRN and XLRH have proximal renal tubular defects in common with Dent's disease, but rickets is absent in XRN, and nephrocalcinosis and moderate renal failure are more notable in XLRH. These three disorders of hypercalciuric nephrolithiasis (Dent's disease, XRN, and XLRH) have all been mapped to chromosome Xp11.22 (5,8,9) and all three have been established to share a common genetic etiology by demonstrating mutations in the renal chloride channel gene, CLCN5 (10).…”

Linkage mapping of a new syndromic form of X-linked mental retardation, MRXS7, associated with obesity

“…15 Several disease genes have been mapped to this region. They include the androgen receptor gene, 16 the XH2 gene, responsible for ATRX syndrome, an X-linked disorder comprising severe psychomotor retardation, genital abnormalities, and alpha-thalassaemia, 17 three genes responsible for eye diseases, [18][19][20] Wiskott-Aldrich syndrome, 21 one form of synovial sarcoma, 22 X-linked nephrolithiasis, 23 and zinc finger genes (ZXDA 24 and four Kruppel type 25 ). These zinc finger genes could be considered candidates for the syndrome described in this paper, and possibly the Wilson syndrome, further supported by earlier findings, showing that disruption of zinc finger genes was involved in human development disorders such as Greig-cephalopolysyndactyly syndrome 26 and Wilms tumour.…”