Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.
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.
Pollak
M R
MR
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Brown
E M
EM
Chou
Y H
YH
Hebert
S C
SC
Marx
S J
SJ
Steinmann
B
B
Levi
T
T
Seidman
C E
CE
Seidman
J G
JG
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
D017931:DNA Primers; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D002118:Calcium