Spectrum of Mutations in Gitelman Syndrome

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 ligationdependent 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.

Differential diagnosis of Bartter syndrome, Gitelman syndrome, and pseudo–Bartter/Gitelman syndrome based on clinical characteristics

“…5,21 By contrast, the clinical manifestations of type III BS and GS may vary and resemble each other. 7,[11][12][13] Furthermore, p-BS/GS is difficult to distinguish from type III BS or GS because its clinical features match those of the latter two diseases. Correctly distinguishing these three diseases based on their clinical characteristics is thus important.…”

“…Some cases of type III BS were previously reported to show features similar to those of GS, including hypomagnesemia and hypocalciuria. 7,[11][12][13] In addition, one report published in 2003 showed that, in a large consanguineous family, both the BS and GS phenotypes were present with the same CLCNKB mutation. 13 In the same year a review article pointed out the phenotypic overlaps between type III BS and GS.…”

“…33 Recent large cohort studies also showed that about 8% of patients with GS have only heterozygous mutations in the NCCT gene; that GS occurs by heterozygous mutations in NCCT-gene haploinsufficiency or dominant-negative effects by hypomorphic alleles remains possible. 12,24 Further study is needed to answer this long-standing question.…”

“…For example, some patients with type III BS may show clinical features of GS, including hypomagnesemia and hypocalciuria, and diuretic tests may fail to differentiate between them. 7,[11][12][13] Moreover, mutations in known disease-related genes have not been identified in some patients with clinically diagnosed BS/GS. This suggests that some acquired conditions may cause a BS/GS-like disorder, or pseudo-BS/GS (p-BS/GS), associated with loss of sodium or chloride in the urine, stool, or vomitus or with chloride-intake deficiency, resulting in clinical symptoms identical to those of BS/GS.…”

Clinical and Genetic Spectrum of Bartter Syndrome Type 3

“…31 Centre Hospitalier Pierre Oudot de Bourgoin-Jallieu, Service 23 de Pédiatrie, Bourgoin-Jallieu, France. 32 Methods: Genetic analyses were performed by direct sequencing and multiplex ligation-7 dependent probe amplification; medical charts were analyzed retrospectively for 115 patients 8 with CLCNKB mutations. Functional analyses were performed in Xenopus laevis oocytes for 9 eight missense and two nonsense mutations.…”