Spectrum of mutations in Gitelman syndrome
(2011) Journal of the American Society of Nephrology — Vol. 22, n° 4, p. 693-703 (2011)
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- Abstract
- Gitelman's syndrome (GS) is a rare, autosomal recessive, salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive NaCl cotransporter (NCC). Because 18 to 40% of suspected GS patients carry only one SLC12A3 mutant allele, large genomic rearrangements may account for unidentified mutations. Here, we directly sequenced genomic DNA from a large cohort of 448 unrelated patients suspected of having GS. We found 172 distinct mutations, of which 100 were unreported previously. In 315 patients (70%), we identified two mutations; in 81 patients (18%), we identified one; and in 52 patients (12%), we did not detect a mutation. In 88 patients, we performed a search for large rearrangements by multiplex ligation-dependent probe amplification (MLPA) and found nine deletions and two duplications in 24 of the 51 heterozygous patients. A second technique confirmed each rearrangement. Based on the breakpoints of seven deletions, nonallelic homologous recombination by Alu sequences and nonhomologous end-joining probably favor these intragenic deletions. In summary, missense mutations account for approximately 59% of the mutations in Gitelman's syndrome, and there is a predisposition to large rearrangements (6% of our cases) caused by the presence of repeated sequences within the SLC12A3 gene.
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Vargas-Poussou, R., Dahan, K., Kahila, D., Venisse, A., Riveira Munoz, E., Debaix, H., Grisart, B., Bridoux, F., Unwin, R., Moulin, B., Haymann, J.-P., Vantyghem, M.-C., Rigothier, C., Dussol, B., Godin, M., Nivet, H., Dubourg, L., Tack, I., Gimenez-Roqueplo, A.-P., et al. (2011). Spectrum of mutations in Gitelman syndrome. Journal of the American Society of Nephrology, 22(4), 693-703. https://doi.org/10.1681/ASN.2010090907 (Original work published 2011)