title: Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5.
abstract: Hypercalciuria is a major cause of nephrolithiasis, and is a common and complex disorder involving genetic and environmental factors. Identification of genetic factors for monogenic forms of hypercalciuria is hampered by the limited availability of large families, and to facilitate such studies, we screened for hypercalciuria in mice from an N-ethyl-N-nitrosourea mutagenesis programme. We identified a mouse with autosomal dominant hypercalciuria (HCALC1). Linkage studies mapped the Hcalc1 locus to a 11.94 Mb region on chromosome 6 containing the transient receptor potential cation channel, subfamily V, members 5 (Trpv5) and 6 (Trpv6) genes. DNA sequence analysis of coding regions, intron-exon boundaries and promoters of Trpv5 and Trpv6 identified a novel T to C transition in codon 682 of TRPV5, mutating a conserved serine to a proline (S682P). Compared to wild-type littermates, heterozygous (Trpv5(682P/+)) and homozygous (Trpv5(682P/682P)) mutant mice had hypercalciuria, polyuria, hyperphosphaturia and a more acidic urine, and ∼10% of males developed tubulointerstitial nephritis. Trpv5(682P/682P) mice also had normal plasma parathyroid hormone but increased 1,25-dihydroxyvitamin D(3) concentrations without increased bone resorption, consistent with a renal defect for the hypercalciuria. Expression of the S682P mutation in human embryonic kidney cells revealed that TRPV5-S682P-expressing cells had a lower baseline intracellular calcium concentration than wild-type TRPV5-expressing cells, suggesting an altered calcium permeability. Immunohistological studies revealed a selective decrease in TRPV5-expression from the renal distal convoluted tubules of Trpv5(682P/+) and Trpv5(682P/682P) mice consistent with a trafficking defect. In addition, Trpv5(682P/682P) mice had a reduction in renal expression of the intracellular calcium-binding protein, calbindin-D(28K), consistent with a specific defect in TRPV5-mediated renal calcium reabsorption. Thus, our findings indicate that the TRPV5 S682P mutant is functionally significant and study of HCALC1, a novel model for autosomal dominant hypercalciuria, may help further our understanding of renal calcium reabsorption and hypercalciuria.
authors: Academic Endocrine Unit, Nuffield Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism-OCDEM, Churchill Hospital, Headington, Oxford, United Kingdom.
authors: Nellie Y
authors: NY
authors: Loh
authors: Liz
authors: L
authors: Bentley
authors: Henrik
authors: H
authors: Dimke
authors: Sjoerd
authors: S
authors: Verkaart
authors: Paolo
authors: P
authors: Tammaro
authors: Caroline M
authors: CM
authors: Gorvin
authors: Michael J
authors: MJ
authors: Stechman
authors: Bushra N
authors: BN
authors: Ahmad
authors: Fadil M
authors: FM
authors: Hannan
authors: Sian E
authors: SE
authors: Piret
authors: Holly
authors: H
authors: Evans
authors: Ilaria
authors: I
authors: Bellantuono
authors: Tertius A
authors: TA
authors: Hough
authors: William D
authors: WD
authors: Fraser
authors: Joost G J
authors: JG
authors: Hoenderop
authors: Frances M
authors: FM
authors: Ashcroft
authors: Steve D M
authors: SD
authors: Brown
authors: René J M
authors: RJ
authors: Bindels
authors: Roger D
authors: RD
authors: Cox
authors: Rajesh V
authors: RV
authors: Thakker
mesh_terms: D000818:Animals; D001483:Base Sequence; D064026:Calbindins; D015220:Calcium Channels / Q000235:genetics*; D002874:Chromosome Mapping; D005799:Genes, Dominant / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D053565:Hypercalciuria / Q000235:genetics* / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D017422:Sequence Analysis, DNA; D050916:TRPV Cation Channels / Q000235:genetics*
chemical_list: D064026:Calbindins; D015220:Calcium Channels; D064030:S100 Calcium Binding Protein G; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse
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