Sporadic hypoparathyroidism caused by de novo gain-of-function mutations of the Ca2+-sensing receptor

Francesco De Luca, Kausik Ray, Edna E. Mancilla, Gao Feng Fan, Karen K. Winer, Pankaj Gore, Allen M. Spiegel, Jeffrey Baron

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Activating mutations of the Ca2+-sensing receptor (CaR) gene have been identified in families with autosomal dominant hypoparathyroidism and in one patient with sporadic hypoparathyroidism. Here, we describe two additional patients with sporadic hypoparathyroidism. One patient presented with mild symptoms at age 18 yr; the other was severely symptomatic from infancy. A heterozygous missense mutation was identified in each patient. One mutation (L773R) involved the fifth transmembrane domain of the CaR, the other (N118K) affected the amino-terminal, extracellular domain. In both cases, the probands' parents lacked the mutation, indicating that the mutations arose de novo. In expression studies the mutations shifted the concentration-response curve to the left and increased maximal activity. We conclude that 1) sporadic hypoparathyroidism can be caused by de novo gain-of-function mutations of the CaR; 2) the phenotype can vary from mild to life-threatening hypocalcemia; 3) gain-of-function mutations can involve not only extracellular regions, as previously reported, but also transmembrane domains of the CaR; and 4) the mechanism of activation can involve both increased receptor sensitivity to Ca2+ and increased maximal signal transduction.

Original languageEnglish (US)
Pages (from-to)2710-2715
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume82
Issue number8
DOIs
Publication statusPublished - Aug 22 1997
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this