Shs. Pearce et al., CALCIUM-SENSING RECEPTOR MUTATIONS IN FAMILIAL BENIGN HYPERCALCEMIA AND NEONATAL HYPERPARATHYROIDISM, The Journal of clinical investigation, 96(6), 1995, pp. 2683-2692
Familial benign hypercalcemia (FBH) and neonatal hyperparathyroidism (
NHPT) are disorders of calcium homeostasis that are associated with mi
ssense mutations of the calcium-sensing receptor (CaR). We have undert
aken studies to characterize such CaR mutations in FBH and NHPT and to
explore methods for their more rapid detection. Nine unrelated kindre
ds (39 affected, 32 unaffected members) with FBH and three unrelated c
hildren with sporadic NHPT were investigated for mutations in the 3,23
4-bp coding region of the CaR gene by DNA sequencing. Six novel hetero
zygous (one nonsense and five missense) mutations were identified in s
ix of the nine PBH kindreds, and two de novo heterozygous missense mut
ations and one homozygous frame-shift mutation were identified in the
three children with NHPT. Our results expand the phenotypes associated
with CaR mutations to include sporadic NHPT, Single-stranded conforma
tional polymorphism analysis was found to be a sensitive and specific
mutational screening method that detected > 85% of these CaR gene muta
tions. The single-stranded conformational polymorphism identification
of CaR mutations may help in the distinction of FBH from mild primary
hyperparathyroidism which can be clinically difficult. Thus, the resul
ts of our study will help to supplement the clinical evaluation of som
e hypercalcemic patients and to elucidate further the structure-functi
on relationships of the CaR.