A novel initial codon mutation of the thiazide-sensitive Na-Cl cotransporter gene in a Japanese patient with Gitelman's syndrome

Abstract

Abstract. We here report a novel mutation of the thiazide-sensitive Na-Cl cotransporter (TSC) (SLC12A3) gene in a Japanese patient with Gitelman's syndrome (GS). GS is characterized by a renal disorder and is associated with hypokalemia, hypomagnesemia, metabolic alkalosis and hypocalciuria arising from the defective tubular reabsorption of magnesium and potassium. This disease is reportedly caused by mutations in the TSC gene. A 52-year-old man was referred to our hospital because of sleeplessness and tinnitus. He exhibited hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis and hyperreninemic hyperaldosteronism. A renal clearance study revealed that the administration of furosemide decreased chloride reabsorption; however, the ingestion of thiazide failed to decrease chloride reabsorption. A diagnosis of GS was made based on the clinical features, laboratory data and renal function test results. Sequencing of the patient's genomic DNA revealed an A to T transition at the initial codon of exon 1 of the TSC gene (c1A>T). Knowledge of this novel mutation may be helpful for understanding the pathophysiology of GS and the function of TSC as well as for providing genetic counseling.

Gitelman's syndrome: a pathophysiological and clinical update

“…The mutation of nature and/or position of the SLC12A3 gene combined with male gender seem to be associated with the severity of the syndrome. This observation is supported by earlier studies showing that the density of NCCT in DCT can be influenced by estrogen in rats [17][18][19].…”

Problems in diagnosing atypical Gitelman’s syndrome presenting with normomagnesaemia

“…We speculate that patient 1 may have an unidentified gene abnormality on the allele in addition to the Thr180Lys mutation 9 . The functional consequence of the mutation in patient 3 is unknown, however it may be speculated that this mutation might change amino acid residues due to alternative initiation of translation at a second, in‐frame ATG present 53 codons downstream, potentially impairing the function of the TSC protein 11 . Patients 4 and 5 were compound heterozygous for two different mutations on both TSC alleles, which is the most common inheritance pattern in GS patients 22,23 .…”

“…This study included five patients (four males and one female) with hypokalaemia from Hokkaido University Hospital, Sapporo Shakai Hoken General Hospital, Sapporo City Hospital, Takikawa City Hospital in Hokkaido, and Yokohama City University Hospital in Yokohama, Japan. The details of two males and one female (patients 1, 2 and 3) were described previously 9–11 . All five patients were on normal diets and not taking either regular medications or supplements that could affect serum electrolytes.…”

“…The details of two males and one female (patients 1, 2 and 3) were described previously. [9][10][11] All five patients were on normal diets and not taking either regular medications or supplements that could affect serum electrolytes. Serum and urinary electrolytes, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured by standard laboratory techniques.…”

Thiazide-sensitive Na<sup>+</sup>–Cl<sup>−</sup> cotransporter: genetic polymorphisms and human diseases

“…More than 50 mutations have been reported in Asian populations [23,24,[27][28][29]42,51,[55][56][57][58]. In particular, Thr60Met is the most prevalent mutant in Asian patients with Gitelman's syndrome [23,24,[27][28][29]42], while in the Gypsy people, Gitelman's syndrome was featured by intron 9 +1G>T [53].…”