A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor

N Engl J Med. 1996 Oct 10;335(15):1115-22. doi: 10.1056/NEJM199610103351505.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amino Acid Sequence
  • Base Sequence
  • Calcium / urine*
  • Child
  • Child, Preschool
  • Diagnosis, Differential
  • Female
  • Humans
  • Hypocalcemia / diagnosis
  • Hypocalcemia / genetics*
  • Hypoparathyroidism / diagnosis
  • Hypoparathyroidism / genetics
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Parathyroid Hormone / blood
  • Pedigree
  • Phenotype
  • Point Mutation*
  • Polymorphism, Single-Stranded Conformational
  • Receptors, Calcium-Sensing
  • Receptors, Cell Surface / genetics*
  • Syndrome


  • Parathyroid Hormone
  • Receptors, Calcium-Sensing
  • Receptors, Cell Surface
  • Calcium

Associated data

  • GENBANK/X81086