title: Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation.
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.
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Andreas
authors.initials: A
authors.lastname: Pasch
authors.forename: Olivier
authors.initials: O
authors.lastname: Bonny
authors.forename: Markus G
authors.initials: MG
authors.lastname: Mohaupt
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Hediger
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Frey
mesh_terms: D000328:Adult; D000818:Animals; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006239:Haplotypes; D006801:Humans; D053565:Hypercalciuria / Q000235:genetics* / Q000378:metabolism; D007669:Kidney Calculi / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010281:Parathyroid Hormone / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D050916:TRPV Cation Channels / Q000235:genetics* / Q000378:metabolism; D014981:Xenopus
chemical_list: D015220:Calcium Channels; D010281:Parathyroid Hormone; D050916:TRPV Cation Channels; C422827:TRPV6 protein, human; D002117:Calcitriol; D002118:Calcium