MUTATIONS IN THE HUMAN CA2+-SENSING RECEPTOR GENE CAUSE FAMILIAL HYPOCALCIURIC HYPERCALCEMIA AND NEONATAL SEVERE HYPERPARATHYROIDISM

被引:797
作者
POLLAK, MR
BROWN, EM
CHOU, YHW
HEBERT, SC
MARX, SJ
STEINMANN, B
LEVI, T
SEIDMAN, CE
SEIDMAN, JG
机构
[1] BRIGHAM & WOMENS HOSP,DEPT MED,DIV ENDOCRINE HYPERTENS,BOSTON,MA 02115
[2] BRIGHAM & WOMENS HOSP,DEPT MED,DIV CARDIOL,BOSTON,MA 02115
[3] HARVARD UNIV,SCH MED,DEPT GENET,BOSTON,MA 02115
[4] HARVARD UNIV,SCH MED,HOWARD HUGHES MED INST,BOSTON,MA 02115
[5] NIDDKD,METAB DIS BRANCH,BETHESDA,MD 20892
[6] UNIV ZURICH,DEPT PEDIAT,CH-8032 ZURICH,SWITZERLAND
关键词
D O I
10.1016/0092-8674(93)90617-Y
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We demonstrate that mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), two inherited conditions characterized by altered calcium homeostasis. The Ca2+-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 elicted large inward currents in response to perfused polyvalent cations; a markedly attenuated response was observed with the mutated protein. We conclude that the mammalian Ca2+-sensing receptor ''sets'' the extracellular Ca2+ level and is defective in individuals with FHH and NSHPT.
引用
收藏
页码:1297 / 1303
页数:7
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