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

Autor: Andreas Pasch, Felix J. Frey, Olivier Bonny, Yoshiro Suzuki, Markus G. Mohaupt, Matthias A. Hediger
Rok vydání: 2008
Předmět:
Adult
Male
medicine.medical_specialty
TRPV6
Calcitriol
Xenopus
Hypercalciuria
030232 urology & nephrology
TRPV Cation Channels
chemistry.chemical_element
Parathyroid hormone
Calcium
Biology
Polymorphism
Single Nucleotide
Kidney Calculi
03 medical and health sciences
0302 clinical medicine
Risk Factors
Internal medicine
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
Middle Aged
Parathyroid Hormone/blood
TRPV Cation Channels/genetics
TRPV Cation Channels/metabolism
Genetics
medicine
Molecular Biology
Genetics (clinical)
030304 developmental biology
0303 health sciences
Voltage-dependent calcium channel
Calcium channel
Haplotype
General Medicine
medicine.disease
Endocrinology
chemistry
Parathyroid Hormone
Calcium Channels
medicine.drug
Zdroj: Human molecular genetics
Human Molecular Genetics, vol. 17, no. 11, pp. 1613-1618
Suzuki, Yoshiro; Pasch, Andreas; Bonny, Olivier; Mohaupt, Markus G; Hediger, Matthias A; Frey, Felix J (2008). Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation. Human molecular genetics, 17(11), pp. 1613-8. Oxford: Oxford University Press 10.1093/hmg/ddn048
DOI: 10.1093/hmg/ddn048
Popis: 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.
Databáze: OpenAIRE
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