A novel gain-of-function mutation (F821L) in the transmembrane domain of calcium-sensing receptor is a cause of severe sporadic hypoparathyroidism.

UNLABELLED: Gain-of-function mutations of the extracellular calcium (Ca(2+)e)-sensing receptor (CaR) have been identified in patients with familial and sporadic hypercalciuric hypocalcaemia. We describe a patient with sporadic severe hypercalciuric hypocalcaemia with undetectable or very low levels of serum parathyroid hormone, carrying a de novo heterozygous missense mutation ( F821L), localized in the sixth transmembrane domain of CaR. Analysis of in vitro functional properties of the mutant receptor to measure Ca(2+)e-evoked changes in intracellular Ca(2+) revealed a leftward shift in the concentration-response curve for the mutant compared to wild-type receptor.
CONCLUSION: the F821Lmutation is therefore a novel gain-of-function mutation which can cause severe hypoparathyroidism. Thiazide diuretics lowered urinary calcium excretion of the patient treated with calcium supplementation and 1alpha-hydroxyvitamin D(3.)