Two Novel Mutations of Thiazide-Sensitive Na-Cl Cotransporter (TSC) Gene in Two Sporadic Japanese Patients with Gitelman Syndrome

Gitelman syndrome is a renal disorder characterized by hypokalemia, hypomagnesemia, metabolic alkalosis and hypocalciuria due to the defective tubular reabsorption of magnesium and potassium. This disease is caused by mutations of thiazide-sensitive Na-Cl cotransporter (TSC) gene. Gitelman syndrome is usually distinguished from Bartter syndrome by the presence of both hypomagnesemia and hypocalciuria. However, a phenotypic overlap is sometimes observed. We encountered two sporadic Japanese patients with Gitelman syndrome and analyzed their TSC gene. These patients were diagnosed as Gitelman syndrome by the typical clinical findings and biochemical abnormalities, such as mild muscular weakness, periodic paralysis, tetany, metabolic alkalosis, hypomagnesemia and hypocalciuria. In patient 1, a novel two base deletion (del TG at nucleotide 731 and 732) in exon 5 and a two base deletion (del TT at nucleotide 2543 and 2544) in exon 21 previously reported in a Japanese patient were identified. The patient 2 had a missense mutation (L623P), that was also identified in Japanese patients, and a novel in-frame 18 base insertion in exon 6 as a heterozygous state. Family analysis of two patients confirmed an autosomal recessive inheritance. In conclusion, we add two new mutations of the TSC gene in Japanese patients with Gitelman syndrome. Because the differential diagnosis between Bartter syndrome and Gitelman syndrome is sometimes difficult, molecular analysis would be a useful diagnostic tool, particularly in unusual cases with phenotypic overlapping.