Abstract
BackgroundGitelman syndrome (GS) is an autosomal recessive disorder caused by genic mutations of SLC12A3 (Solute carrier family 12 member 3), which encodes the Na-Cl cotransporter (NCC), and presents with characteristic metabolic abnormalities, including hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. In this study, we report a case of a GS pedigree, including analysis of GS-associated gene mutations.MethodsWe performed next-generation sequencing analysis and Sanger sequencing to explore the SLC12A3 mutations in a GS pedigree that included a 35-year-old female patient with GS and five family members within three generations. Furthermore, we summarized their clinical manifestations and analyzed laboratory parameters related to GS.ResultsThe female proband (the patient with GS) presented with intermittent fatigue and transient periods of tetany, along with significant hypokalemia, hypomagnesemia, and hypocalciuria. All other members of the pedigree had normal laboratory results without obvious GS-related symptoms. Genetic analysis of the SLC12A3 gene identified two novel missense mutations (c.1919A > G, p.N640S in exon 15; c.2522A > G, p.D841G in exon 21) in the patient with GS. Moreover, we demonstrated that her mother, younger maternal uncle, and cousin were carriers of one mutation (c.1919A > G), and her father was the carrier of the other (c.2522A > G).ConclusionThis is the first report of these two novel pathogenic variants of SLC12A3 and their contribution to GS. Further functional studies are particularly warranted to explore the underlying molecular mechanisms.
Highlights
Gitelman syndrome (GS) is an autosomal recessive disorder caused by genic mutations of SLC12A3 (Solute carrier family 12 member 3), which encodes the Na-Cl cotransporter (NCC), and presents with characteristic metabolic abnormalities, including hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria
Gitelman et al first described Gitelman syndrome (GS) as an autosomal recessive disorder presenting with characteristic metabolic abnormalities [1], including hypokalemia, metabolic alkalosis, hypomagnesaemia, hypocalciuria, and renin-angiotensin-aldosterone system (RAAS) activation, along with normal or low blood pressure
The electrolyte disturbances did not resolve completely, given the fact that treatment could only increase the level of potassium and magnesium up to the lower limit of the normal range
Summary
Gitelman syndrome (GS) is an autosomal recessive disorder caused by genic mutations of SLC12A3 (Solute carrier family 12 member 3), which encodes the Na-Cl cotransporter (NCC), and presents with characteristic metabolic abnormalities, including hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. Gitelman et al first described Gitelman syndrome (GS) as an autosomal recessive disorder presenting with characteristic metabolic abnormalities [1], including hypokalemia, metabolic alkalosis, hypomagnesaemia, hypocalciuria, and renin-angiotensin-aldosterone system (RAAS) activation, along with normal or low blood pressure. A long-term follow-up of one patient who suffered from GS since she was 2.5 years old revealed that it was possible to obtain satisfactory growth and physical development with proper treatment [4]. It was argued that patients with earlyonset and severe manifestations could suffer from
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