Exonic Mutations in the SLC12A3 Gene Cause Exon Skipping and Premature Termination in Gitelman Syndrome

Takeuchi, Yoichi; Mishima, Eikan; Shima, Hisato; Akiyama, Yasutoshi; Suzuki, Chitose; Suzuki, Takehiro; Kobayashi, Toshihide; Suzuki, Yôichi; Nakayama, Tomohiro; Takeshima, Yasuhiro; Vázquez, Norma; Ito, Sadayoshi; Gamba, Gerardo; Abe, Takaaki

doi:10.1681/asn.2013091013

Cited by 39 publications

(37 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5 To date, >350 mutations scattered throughout SLC12A3 have been identified in GS patients. 6,7 The majority of patients are compound heterozygous for SLC12A3 mutations, but a significant number of GS patients are found to carry only a single SLC12A3 mutation.…”

mentioning

confidence: 99%

Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Blanchard

Böckenhauer

Bolignano

et al. 2017

Kidney International

274

346

View full text Add to dashboard Cite

Gitelman syndrome (GS) is a rare, salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The disease is recessively inherited, caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is usually detected during adolescence or adulthood, either fortuitously or in association with mild or nonspecific symptoms or both. The disease is characterized by high phenotypic variability and a significant reduction in the quality of life, and it may be associated with severe manifestations. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management. We report here on the current state of knowledge related to the diagnostic evaluation, follow-up, management, and treatment of GS; identify knowledge gaps; and propose a research agenda to substantiate a number of issues related to GS. This expert consensus statement aims to establish an initial framework to enable clinical auditing and thus improve quality control of care.

show abstract

mentioning

confidence: 99%

Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Blanchard

Böckenhauer

Bolignano

et al. 2017

Kidney International

274

346

View full text Add to dashboard Cite

show abstract

“…Since the new mutation does not seem to affect the splicing site acceptor recognition, it could result in a frame-shift with a premature stop of the translation and a clear loss-of-function. However, the possibility of skipping of exon 2 cannot be completely discarded, since that mechanism has been experimentally verified for the mutation c.1926delC located at the 5’ end of exon 16 of SLC12A3 [15]. …”

Section: Discussionmentioning

confidence: 99%

New SLC12A3 disease causative mutation of Gitelman’s syndrome

Grillone¹,

Menniti²,

Bombardiere³

et al. 2016

WJN

View full text Add to dashboard Cite

Gitelman’s syndrome (GS) is a salt-losing tubulopathy with an autosomal recessive inheritance caused by mutations of SLC12A3, which encodes for the thiazide-sensitive NaCl cotransporter. In this study we report a new mutation of SLC12A3 found in two brothers affected by GS. Hypokalemia, hypocalciuria and hyper-reninemia were present in both patients while hypomagnesemia was detected only in one. Both patients are compound heterozygotes carrying one well known GS associated mutation (c.2581 C > T) and a new one (c.283delC) in SLC12A3 gene. The new mutation results in a possible frame-shift with a premature stop-codon (pGln95ArgfsX19). The parents of the patients, heterozygous carriers of the mutations found in SLC12A3, have no disease associated phenotype. Therefore, the new mutation is causative of GS.

show abstract

“…More recent data suggest diuretics have a direct interaction on renal UA handling through the voltage-driven UA transporter hNPT4/SLC17A3 12 , as well as the cyclic nucleotide transporter, MRP4/ABCC4 13 . Interestingly, Gitelman syndrome has recently been described as associated with mutations in the UA transporter gene, SLC17A3 14 . A detailed mechanism of thiazide diuretic effect on renal handling of UA is depicted in Figure 1.…”

Section: To the Editormentioning

confidence: 99%