Insertion of an Alu sequence in the Ca(2+)-sensing receptor gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

Abstract

Missense mutations in the calcium-sensing receptor (CaR) gene have previously been identified in patients with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). We studied family members of a Nova Scotian deme expressing both FHH and NSHPT and found, by PCR amplification of CaR gene exons, that FHH individuals were heterozygous and NSHPT individuals were homozygous for an abnormally large exon 7. This is due to an insertion at codon 877 of an Alu-repetitive element of the predicted-variant/human-specific-1 subfamily. It is in the opposite orientation to the CaR gene and contains an exceptionally long poly(A) tract. Stop signals are introduced in all reading frames within the Alu sequence, leading to a predicted shortened mutant CaR protein. The loss of the majority of the CaR carboxyl-terminal intracellular domain would dramatically impair its signal transduction capability. Identification of the specific mutation responsible for the FHH/NSHPT phenotype in this community will allow rapid testing of at-risk individuals.