A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.
BACKGROUND
The calcium-sensing receptor regulates the secretion of parathyroid hormone in response to changes in extracellular calcium concentrations, and mutations that result in a loss of function of the receptor are associated with familial hypocalciuric hypercalcemia. Mutations involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hypercalciuria.


METHODS
We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor. The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the calcium-sensing-receptor gene were identified by DNA-sequence analysis and expressed in human embryonic kidney cells (HEK-293).


RESULTS
Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease. Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P=0.02 to P<0.001) lower than those required for the wild-type receptor.


CONCLUSIONS
Gain-of-function mutations in the calcium-sensing receptor are associated with a familial syndrome of hypocalcemia with hypercalciuria that needs to be distinguished from hypoparathyroidism.
Pearce
S H
SH
Medical Research Council Molecular Endocrinology Group, Royal Postgraduate Medical School, London, United Kingdom.
Williamson
C
C
Kifor
O
O
Bai
M
M
Coulthard
M G
MG
Davies
M
M
Lewis-Barned
N
N
McCredie
D
D
Powell
H
H
Kendall-Taylor
P
P
Brown
E M
EM
Thakker
R V
RV
D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D002118:Calcium / Q000652:urine*; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D006996:Hypocalcemia / Q000175:diagnosis / Q000235:genetics*; D007011:Hypoparathyroidism / Q000175:diagnosis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010281:Parathyroid Hormone / Q000097:blood; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000235:genetics*; D013577:Syndrome
D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D002118:Calcium