2 NOVEL MISSENSE MUTATIONS IN CALCIUM-SENSING RECEPTOR GENE ASSOCIATED WITH NEONATAL SEVERE HYPERPARATHYROIDISM

Familial hypocalciuric hypercalcemia (FHH) is characterized by lifelon g asymptomatic hypercalcemia without PTH hypersecretion and is inherit ed as an autosomal dominant trait with near 100% penetrance. In contra st, neonatal severe hyperparathyroidism (NSHPT) is a life-threatening disorder characterized by marked hypercalcemia and PTH hypersecretion. FHH/NSHPT results from inactivating mutations of the human calcium-se nsing receptor (Casr) gene on chromosome 3q13.3-24. Nearly 30 differen t mutations of the Casr gene associated with FHH/NSHPT have been repor ted previously. In this report, genetic analysis of 1 Japanese NSHPT f amily revealed 2 novel mutations at codon 185 (CGA-->TGA/Agr-->Ter) in exon 4 of the Casr gene and at codon 670 (GGG-->GAG/Gly-->Glu) in exo n 7. The Agr(185)Ter change was shown to occur in the proband's unaffe cted father and paternal grandmother as well as in the proband. The ot her mutation in exon 7 was shown in the proband's unaffected mother of Philippine origin as well as in the proband. This family is the first case of manifestation of more than 1 mutation in a proband's chromoso mes; 1 mutation was obtained from the unaffected father, and the other was from the unaffected mother. Our observations have given us import ant keys to help elucidate the structure-function relationships of the Casr.