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Human Molecular Genetics Advance Access published online on February 13, 2008
Human Molecular Genetics, 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 Suzuki1,3, Andreas Pasch2,3, Olivier Bonny2, Markus G. Mohaupt2, Matthias A. Hediger1,* and Felix J. Frey2

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

* Address correspondence to: Prof. Dr. Matthias A. Hediger, Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland, TEL: +41 31 631 4129, FAX: +41 31 631 3410, E-mail: matthias.hediger{at}mci.unibe.ch

Received December 19, 2007; Revised February 10, 2008; 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 vs. 3.61 ± 1.01 pmol/min/oocyte for ancestral vs. 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.

3 These authors contributed equally to the work.


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