A novel compound heterozygous mutation of SLC12A3 gene in a pedigree with Gitelman syndrome and literature review
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Genes & Genomics https://doi.org/10.1007/s13258-020-00960-6
RESEARCH ARTICLE
A novel compound heterozygous mutation of SLC12A3 gene in a pedigree with Gitelman syndrome and literature review Minglan Yang1 · Ying Dong1 · Jianqing Tian1 · Li Yan1 · Yawen Chen1 · Huiying Qiu1 · Wei Liu1 · Yaomin Hu1 Received: 24 February 2020 / Accepted: 15 June 2020 © The Genetics Society of Korea 2020
Abstract Background Gitelman syndrome (GS) is a tubulopathy characterized by hypokalemia, hypomagnesemia, hypocalciuria and metabolic alkalosis, which is caused by mutations in SLC12A3 gene. Objective The objective of this study was to investigate the mutation of SLC12A3 gene in a pedigree with GS and analyzed the clinical manifestations. Methods Next-generation sequencing and Sanger sequencing were performed to explore the mutations of SLC12A3 gene in a GS pedigree that included a 59-year-old male GS patient and a total of 11 family members within three generations. Results A novel compound heterozygous mutation of SLC12A3 gene (c.1712T > C in exon14 and c.2986_2987ins GCT in exon26) was identified by genetic testing in the proband. Moreover, we demonstrated that two brothers shared the same heterozygous mutation with the proband, but only one brother had the GS related symptoms. His nephew was the carrier of one mutation (c.1712T > C), and one of his brother, his sister and niece were carriers of the other (c.2986_2987ins GCT). Conclusions This is the first study to report the novel pathogenic compound heterozygous mutation of SLC12A3 gene in GS. Our result further supports the lack of phenotype–genotype correlations in GS. Further functional studies are required to investigate pathophysiologic mechanisms of GS. Keywords Gitelman syndrome · Hypokalemia · SLC12A3 gene · Pedigree
Introduction GS is an autosomal recessive inherited tubular disease characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. GS was found to be associated with Minglan Yang and Ying Dong contribute equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13258-020-00960-6) contains supplementary material, which is available to authorized users.
the mutations in the SLC12A3 gene, which encodes the thiazide-sensitive sodium-chloride cotransporter (NCCT) (Xia et al. 2017). Muscle weakness is the most common symptom of patients with GS, but some patients are asymptomatic or have mild discomfort (Subasinghe et al. 2017). GS has been considered to be a benign tubular disorder for a long time, usually diagnosed during routine check-up (Blanchard et al. 2017). However, this view has been challenged as GS has been found to be associated with growth retardation, diabetes, congestive heart failure, and ventricular arrhythmia
* Wei Liu [email protected]
Li Yan [email protected]
* Yaomin Hu [email protected]
Yawen Chen [email protected]
Minglan Yang [email protected]
Huiying Qiu [email protected]
Ying Dong [email protected]
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Jianqing Tian 449
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