A new missense mutation in the calcium-sensing receptor in familial benign hypercalcaemia associated with partial lipoatrophy and insulin resistant diabetes.

We studied two patients (a 54-year-old woman and her 16-year-old son) with familial benign hypocalciuric hypercalcaemia (FBHH) associated with severe insulin resistant diabetes in the context of a partial lipodystrophic syndrome. Sequencing of the entire coding sequence of the calcium-sensing receptor (CaR) gene revealed a novel heterozygous mutation at codon 395, leading to the substitution of a cysteine by an arginine residue (Cys395Arg) in the extracellular ligand-binding domain. This mutation was absent in two normocalcaemic relatives and in 54 control subjects. It was recently shown, in transfection studies, that the substitution of this amino acid results in incomplete receptor processing, a severe decrease in cell surface expression and altered signal transduction (Fan et al., 1998). This mutation is therefore likely to be responsible of the FBHH phenotype. A pathophysiological link between this mutation and insulin resistance remains unclear.