期刊
HUMAN MOLECULAR GENETICS
卷 21, 期 12, 页码 2768-2778出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/dds105
关键词
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资金
- Medical Research Council (MRC), UK [G9825289/2004, G1000467/2010]
- Portuguese Foundation for Science and Technology [BD/12415/2003]
- Medical Research Council [G84/6423, G1000467, G9825289] Funding Source: researchfish
- MRC [G1000467, G84/6423, G9825289] Funding Source: UKRI
The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that has an extracellular bilobed venus flytrap domain (VFTD) predicted to contain five calcium (Ca-2)-binding sites. To elucidate the structurefunction relationships of the VFTD, we investigated 294 unrelated probands with familial hypocalciuric hypercalcaemia (FHH), neonatal severe primary hyperparathyroidism (NSHPT) or autosomal dominant hypocalcaemic hypercalciuria (ADHH) for CaSR mutations and performed in vitro functional expression studies and three-dimensional modelling of mutations involving the VFTD. A total of 70 different CaSR mutations were identified: 35 in FHH, 10 in NSHPT and 25 in ADHH patients. Furthermore, a CaSR variant (Glu250Lys) was identified in FHH and ADHH probands and demonstrated to represent a functionally neutral polymorphism. NSHPT was associated with a large proportion of truncating CaSR mutations that occurred in the homozygous or compound heterozygous state. Thirty-four VFTD missense mutations were identified, and 18 mutations were located within 10 of one or more of the predicted Ca-2-binding sites, particularly at the VFTD cleft, which is the principal site of Ca-2 binding. Mutations of residues 173 and 221, which are located at the entrance to the VFTD cleft binding site, were associated with both receptor activation (Leu173Phe and Pro221Leu) and inactivation (Leu173Pro and Pro221Gln), thereby highlighting the importance of these residues for entry and binding of Ca-2 by the CaSR. Thus, these studies of disease-associated CaSR mutations have further elucidated the role of the VFTD cleft region in Ca-2 binding and the function of the CaSR.
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