INSERTION OF AN ALU SEQUENCE IN THE CA2-SENSING RECEPTOR GENE IN FAMILIAL HYPOCALCIURIC HYPERCALCEMIA AND NEONATAL SEVERE HYPERPARATHYROIDISM()

Missense mutations in the calcium-sensing receptor (CaR) gene have pre viously been identified in patients with familial hypocalciuric hyperc alcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). We stud ied family members of a Nova Scotian deme expressing both FHH and NSHP T and found, by PCR amplification of CaR gene exons, that FHH individu als were heterozygous and NSHPT individuals were homozygous for an abn ormally large exon 7. This is due to an insertion at codon 877 of an A lu-repetitive element of the predicted-variant/human-specific-1 subfam ily. 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 shorten ed mutant CaR protein. The loss of the majority of the CaR carboxyl-te rminal intracellular domain would dramatically impair its signal trans duction capability. Identification of the specific mutation responsibl e for the FHH/NSHPT phenotype in this community will allow rapid testi ng of at-risk individuals.