A new missense mutation in the calcium-sensing receptor in familial benignhypercalcaemia 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 syndr ome. Sequencing of the entire coding sequence of the calcium-sensing recept or (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 normo calcaemic relatives and in 54 control subjects. It was recently shown, in t ransfection studies, that the substitution of this amino acid results in in complete receptor processing, a severe decrease in cell surface expression and altered signal transduction (Fan ef al., 1998), This mutation is theref ore likely to be responsible of the FBHH phenotype, A pathophysiological li nk between this mutation and insulin resistance remains unclear.