title: Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.
abstract: We demonstrate that mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), two inherited conditions characterized by altered calcium homeostasis. The Ca(2+)-sensing receptor belongs to the superfamily of seven membrane-spanning G protein-coupled receptors. Three nonconservative missense mutations are reported: two occur in the extracellular N-terminal domain of the receptor; the third occurs in the final intracellular loop. One mutated receptor identified in FHH individuals was expressed in X. laevis oocytes. The expressed wild-type receptor elicited large inward currents in response to perfused polyvalent cations; a markedly attenuated response was observed with the mutated protein. We conclude that the mammalian Ca(2+)-sensing receptor "sets" the extracellular Ca2+ level and is defective in individuals with FHH and NSHPT.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.
authors.forename: M R
authors.initials: MR
authors.lastname: Pollak
authors.forename: E M
authors.initials: EM
authors.lastname: Brown
authors.forename: Y H
authors.initials: YH
authors.lastname: Chou
authors.forename: S C
authors.initials: SC
authors.lastname: Hebert
authors.forename: S J
authors.initials: SJ
authors.lastname: Marx
authors.forename: B
authors.initials: B
authors.lastname: Steinmann
authors.forename: T
authors.initials: T
authors.lastname: Levi
authors.forename: C E
authors.initials: CE
authors.lastname: Seidman
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002118:Calcium / Q000502:physiology; D003001:Cloning, Molecular; D017931:DNA Primers / Q000737:chemistry; D015870:Gene Expression; D005796:Genes; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics*; D006961:Hyperparathyroidism / Q000151:congenital / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000235:genetics*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D017931:DNA Primers; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D002118:Calcium