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Human Molecular Genetics Advance Access originally published online on February 13, 2008
Human Molecular Genetics 2008 17(11):1613-1618; doi:10.1093/hmg/ddn048
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Yoshiro Suzuki1,{dagger}, Andreas Pasch2,{dagger}, Olivier Bonny2, Markus G. Mohaupt2, Matthias A. Hediger1,* and Felix J. Frey2

1 Institute of Biochemistry and Molecular Medicine 2 Department of Nephrology and Hypertension, University of Bern, Bern, Switzerland

* To whom correspondence should be addressed at: Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland. Email: matthias.hediger{at}mci.unibe.ch

Received December 19, 2007; Accepted February 10, 2008

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 45Ca2+ 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.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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