Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation.

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Version: Final published version
Serval ID
serval:BIB_544EC70C9D5E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation.
Journal
Human Molecular Genetics
Author(s)
Suzuki Y., Pasch A., Bonny O., Mohaupt M.G., Hediger M.A., Frey F.J.
ISSN
1460-2083[electronic], 0964-6906[linking]
Publication state
Published
Issued date
2008
Peer-reviewed
Oui
Volume
17
Number
11
Pages
1613-1618
Language
english
Abstract
The rate-limiting step of dietary calcium absorption in the intestine requires the brush border calcium entry channel TRPV6. The TRPV6 gene was completely sequenced in 170 renal calcium stone patients. The frequency of an ancestral TRPV6 haplotype consisting of three non-synonymous polymorphisms (C157R, M378V, M681T) was significantly higher (P = 0.039) in calcium stone formers (8.4%; derived = 502, ancestral = 46) compared to non-stone-forming individuals (5.4%; derived = 645, ancestral = 37). Mineral metabolism was investigated on four different calcium regimens: (i) free-choice diet, (ii) low calcium diet, (iii) fasting and (iv) after a 1 g oral calcium load. When patients homozygous for the derived haplotype were compared with heterozygous patients, no differences were found with respect to the plasma concentrations of 1,25-vitamin D, PTH and calcium, and the urinary excretion of calcium. In one stone-forming patient, the ancestral haplotype was found to be homozygous. This patient had absorptive hypercalciuria. We therefore expressed the ancestral protein (157R+378V+681T) in Xenopus oocytes and found a significantly enhanced calcium permeability when tested by a (45)Ca(2+) uptake assay (7.11 +/- 1.93 versus 3.61 +/- 1.01 pmol/min/oocyte for ancestral versus derived haplotype, P < 0.01). These results suggest that the ancestral gain-of-function haplotype in TRPV6 plays a role in calcium stone formation in certain forms of absorptive hypercalciuria.
Keywords
Adult, Animals, Calcitriol/blood, Calcium/analysis, Calcium/blood, Calcium Channels/genetics, Calcium Channels/metabolism, Female, Haplotypes, Humans, Hypercalciuria/genetics, Hypercalciuria/metabolism, Kidney Calculi/chemistry, Kidney Calculi/genetics, Male, Middle Aged, Parathyroid Hormone/blood, Polymorphism, Single Nucleotide, Risk Factors, TRPV Cation Channels/genetics, TRPV Cation Channels/metabolism, Xenopus
Pubmed
Web of science
Open Access
Yes
Create date
27/03/2009 11:48
Last modification date
20/08/2019 14:09
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