Familial hypocalciuric hypercalcemia (FHH) is generally characterized by lifelong hypercalcemia without hypercalciuria and is inherited in an autosomal dominant manner. Affected individuals show abnormal parathyroid and renal responses to changes in the extracellular calcium concentration. A Japanese FHH family was screened for mutations in the Ca(2+)-sensing receptor gene by the polymerase chain reaction and single strand conformation polymorphism. The proband with hypercalcemia showed an abnormal pattern in exon 1 of the gene, whereas her two sisters with normocalcemia showed a normal pattern. The consanguineous parents with borderline serum calcium concentrations showed both patterns. Nucleotide sequence analysis identified a G-->C point mutation at nucleotide 118 that resulted in the conversion of the normal codon for proline into a codon for alanine at amino acid 40 (numbered according to the bovine complementary DNA). The proband was homozygous for the mutation, and the parents were heterozygous. These results imply that this mutation in the human Ca(2+)-sensing receptor gene causes FHH and that the dosage of the gene defect determines disease phenotype.
A missense mutation in the Ca(2+)-sensing receptor (CaSR) gene was previously identified in a Japanese family with familial hypocalciuric hypercalcemia. Five members of this family with the mutation in the CaSR gene also showed abnormal glucose tolerance, whereas family members homozygous for the wildtype CaSR gene were normal in this respect. The potential relation between mutations in the CaSR gene and the incidence of diabetes mellitus was therefore investigated in 27 non-insulin dependent diabetic and 40 normal Japanese subjects. Each exon of the CaSR gene was amplified by the polymerase chain reaction and subjected to single-strand conformation polymorphism (SSCP) analysis. The region of the gene containing the sixth exon showed three distinct patterns on SSCP analysis in both diabetic patients and normal subjects. Direct sequencing of DNA revealed a T/C polymorphism in the fifth intron. The TT genotype was apparent in 59.3% of diabetic patients and in 45.0% of normal subjects. The CC genotype was present in 25.9% of diabetics and in 22.5% of normal subjects. The diabetic patients were divided into three groups on the basis of genotype for the polymorphism (TT, TC, or CC). However, there was no significant difference among the three groups with regard to the method of therapy, the incidence or severity of diabetic complications, duration or family history of disease, HbA1c level, or laboratory data. The polymorphism in the fifth intron of the CaSR gene does not therefore appear to be associated with non-insulin dependent diabetes mellitus.
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