Two Novel Missense Mutations in Calcium-Sensing Receptor Gene Associated with Neonatal Severe Hyperparathyroidism¹

Abstract

Familial hypocalciuric hypercalcemia (FHH) is characterized by lifelong asymptomatic hypercalcemia without PTH hypersecretion and is inherited as an autosomal dominant trait with near 100% penetrance. In contrast, 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-sensing receptor (Casr) gene on chromosome 3q13.3-24. Nearly 30 different mutations of the Casr gene associated with FHH/NSHPT have been reported previously. In this report, genetic analysis of 1 Japanese NSHPT family revealed 2 novel mutations at codon 185 (CGA-->TGA/Arg-->Ter) in exon 4 of the Casr gene and at codon 670 (GGG-->GAG/Gly-->Glu) in exon 7. The Arg185Ter change was shown to occur in the proband's unaffected father and paternal grandmother as well as in the proband. The other 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 chromosomes; 1 mutation was obtained from the unaffected father, and the other was from the unaffected mother. Our observations have given us important keys to help elucidate the structure-function relationships of the Casr.

Functional Importance of the Ala116–Pro136 Region in the Calcium-sensing Receptor

“…Shown is the topology of CaR with the inactivating mutations (black circles) identified in individuals with familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism and the activating mutations (gray squares) identified in individuals with autosomal dominant hypocalcemia (14,(33)(34)(35)(36)(37)(51)(52)(53) Fig. 2.…”

Is calcium signaling relevant for long bone growth?

“…Classical NSHPT is caused by homozygous inactivating mutations of the calcium sensing receptor (CaSR) gene [4], with only few cases described so far who were heterozygous for a de novo mutation, all of them with a milder disease phenotype than in classical NSPHT [3,5,6]. About 84 cases of NSHPT have been described since 1964 to the present [1,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. Other NSHPT adults successfully treated into adulthood have been reported [14,15], mostly lacking an uninterrupted clinical, radiologic, and laboratory follow-up.…”

“…Early radiologic findings in this disease include bony demineralization, pathologic fractures of long bones and ribs (in 55% of cases), subperiosteal resorption (in 45% of cases), rib fractures and rachitic changes (in 30% of cases) [18,24]. Infants with NSHPT often exhibit polyuria, dehydration and hypotonia associated with a history of failure to thrive, respiratory distress, irritability, lethargy, constipation, and delayed neuropsychological development [2,14,25,26].…”