GCMB mutation in familial isolated hypoparathyroidism with residual secretion of parathyroid hormone

Isolated hypoparathyroidism is an uncommon metabolic disorder characterized by hypocalcemia and hyperphosphatemia, with absent or low levels of PTH. It may present as an apparently sporadic disorder or may be transmitted in families as a genetic trait. Mutations of the calcium-sensing receptor gene and of the preproPTH gene have been reported in occasional cases, and a mutation of the parathyroid-specific transcription factor GCMB gene has been reported in one familial case. We report a second family with isolated hypoparathyroidism and a GCMB mutation. The patients were two siblings from asymptomatic, first-cousin parents, indicating autosomal recessive inheritance. The mutation consisted of the substitution of a glycine residue with a serine at position 63 (G63S) in the DNA-binding GCM domain of GCMB. Functional studies in transfected cells showed that the mutation caused loss of GCMB function, as it abolished transactivation capacity, despite normal subcellular localization, protein stability, and DNA-binding specificity. Contrary to the previously reported family, our patients displayed low but clearly detectable levels of PTH in plasma. This residual hormone secretion probably results from a very small residual activity of the G63S mutant GCMB.