Jap et al. (2001) studied a 79-year-old male with hypocalciuric hypercalcemia (145980) without sibs or children. DNA sequence analysis of the CASR gene showed that the proband was heterozygous for a CGA-to-TGA transition in exon 7 of the CASR gene that encoded an arg648-to-ter (R648X) mutation. This mutation, located in the C terminus of the first intracellular loop of the calcium-sensing receptor, predicts a markedly truncated protein. The mutation was not found in a control group of 50 normal Chinese subjects in Taiwan.
Ward et al. (2004) found this mutation in compound heterozygosity with a G94X truncation of the receptor (601199.0042) in an Australian infant with neonatal severe hyperparathyroidism (NSHPT; 239200). Confocal microscopy demonstrated that the R648X receptor was present in the cytoplasm and also associated with the cell membrane. Functional assays in which R648X and wildtype receptor were cotransfected into HEK293 cells demonstrated a reduction in wildtype Ca(2+) responsiveness by the R648X receptor, even at physiologic Ca(2+) levels, thus simulating familial hypocalciuric hypercalcemia (145980) in relatives of the infant who were heterozygous for the R648X mutation. The R648X receptor alone was nonresponsive to Ca(2+).
