A large homozygous or heterozygous in-frame deletion within the calcium-sensing receptor's carboxylterminal cytoplasmic tail that causes autosomal dominant hypocalcemia

Autosomal dominant hypocalcemia (ADH) can result from heterozygous missense activating mutations of the calcium-sensing receptor (CaSR) gene, a G-prot ein-coupled receptor playing key roles in mineral ion metabolism. We now de scribe an ADH kindred of three generations caused by a novel CaSR mutation, a large in-frame deletion of 181 amino acids within its carboxylterminal-t ail from S895 to V1075. Interestingly, the affected grandfather is homozygo us for the deletion but no more severely affected than heterozygous affecte d individuals. Functional properties of mutant and wild-type (WT) CaSRs wer e studied in transiently transfected, fura-a-loaded human embryonic kidney (HEK293) cells. The mutant receptor exhibited a gain-of-function, but there was no difference between cells transfected with mutant complementary DNA alone or cotransfected with mutant and WT complementary DNAs, consistent wi th the similar phenotypes of heterozygous and homozygous family members. Th erefore, this activating deletion may exert a dominant positive effect on t he WT CaSR. The mutant receptor's cell surface expression was greater than that of the WT CaSR, potentially contributing to its gain-of-function. This novel mutation in the CaSR gene provides the first known examples of a lar ge naturally occurring deletion within a G-protein-coupled receptor's carbo xylterminal-tail and of a homozygous, affected individual with ADH.