New SLC12A3 disease causative mutation of Gitelman’s syndrome

Abstract

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.

Recurrent Episodes of Hypokalaemia during Treatment with Inhaled Beta-2 Agonist Revealing Gitelman Syndrome, an Uncommon Clinical Entity

“…Although the majority of mutations in Gitelman syndrome patients were found in SLC12A3, in a small percentage of subjects mutations in the CLCNKB gene, coding for the chloride channel Kb, were demonstrated to cause the disease. In addition, a relevant percentage of Gitelman syndrome clinical cases are heterozygous carriers or do not show any mutations in SLC12A3 [2,3,5] and perhaps this explains the wide range of variability in clinical presentation, and the presence of alternative routes for chloride to exit the DCT cell have been evoked. Adequate diagnosis and treatment are important, since prolonged hypokalaemia can lead to renal damage including interstitial nephritis, tubular atrophy, interstitial fibrosis and acute renal failure.…”

“…Special attention should be given to those cases with abnormal renal losses. Gitelman syndrome is one of the causes of hypokalaemia, with an estimated prevalence of 1:40,000 [1,2] . Serum potassium between 3 and 3.5 mmol/l rarely causes symptoms; however, levels below 3 mmol/l often result in muscle weakness, cramps, fasciculations, paralytic ileus, hypoventilation, arterial hypotension and in severe cases, rhabdomyolysis, tetany, paralysis and respiratory failure.…”

“…Special attention should be given to those cases with abnormal renal losses. Gitelman syndrome is one of the causes of hypokalaemia, with an estimated prevalence of 1:40,000 [ 1 , 2 ] .…”

Novel SLC12A3 mutation in Gitelman syndrome

“…To date, around 250 mutations, scattered throughout SLC12A3, have been identified in GS patients. The majority of patients are compound heterozygotes for SLC12A3 mutations, but a significant number of GS patients are found to carry only a single SLC12A3 mutation, most likely due to failure to identify the second allele mutation 11–13. The SLC12A3 mutations can be classified into five different classes according to the mechanisms that lead to diminished or absent cotransporter activity 10 12–14…”

Research Article A novel homozygous stop gain mutation in SLC12A3 gene cause Gitelman syndrome in Saudi consanguineous family

“…Often in many cases it has a long asymptomatic period and frequently discovered incidentally after adolescence (Kim et al, 2016). The prevalence of GS is around 1 in 40000 Caucasians (Grillone et al, 2016). GS is caused by pathogenic mutation in the solute carrier family 12-member 3 (SLC12A3) gene that encodes thiazide-sensitive sodium-chloride cotransporter and to date more than 400 deleterious mutations have been identified in SLC12A3 gene so far (Nozu et al, 2014).…”