Autosomal Dominant Hypercalciuria in a Mouse Model Due to a Mutation of the Epithelial Calcium Channel, TRPV5.docVIP

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Autosomal Dominant Hypercalciuria in a Mouse Model Due to a Mutation of the Epithelial Calcium Channel, TRPV5.doc

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Autosomal Dominant Hypercalciuria in a Mouse Model Due to a Mutation of the Epithelial Calcium Channel, TRPV5

AutosomalDominantHypercalciuriainaMouseModel DuetoaMutationoftheEpithelialCalciumChannel, TRPV5 NellieY.Loh1,LizBentley2.,HenrikDimke3.,SjoerdVerkaart3,PaoloTammaro4,CarolineM.Gorvin1, MichaelJ.Stechman1,BushraN.Ahmad1,FadilM.Hannan1,SianE.Piret1,HollyEvans5, IlariaBellantuono5,TertiusA.Hough2,WilliamD.Fraser6,JoostG.J.Hoenderop3,FrancesM.Ashcroft4, SteveD.M.Brown2,Rene′ J.M.Bindels3,RogerD.Cox2,RajeshV.Thakker1* 1Academic Endocrine Unit, Nuffield Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital,Headington,Oxford,UnitedKingdom,2MRCMammalianGeneticsUnitandMaryLyonCentre,MedicalResearchCouncil,Harwell,Oxfordshire,UnitedKingdom, 3DepartmentofPhysiology,NijmegenCentreforMolecularLifeSciences,RadboudUniversityNijmegenMedicalCentre,Nijmegen,TheNetherlands,4Departmentof Physiology,AnatomyandGenetics,UniversityofOxford,Oxford,UnitedKingdom,5AcademicUnitofBoneBiology,UniversityofSheffield,TheMedicalSchool,Sheffield, UnitedKingdom,6FacultyofMedicalandHealthSciences,UniversityofEastAnglia,NorwichResearchPark,Norwich,UnitedKingdom Abstract Hypercalciuria is a major cause of nephrolithiasis, and is a common and complex disorder involving genetic and environmentalfactors.Identificationofgeneticfactorsformonogenicformsofhypercalciuriaishamperedbythelimited availability of large families, and to facilitate such studies, we screened for hypercalciuria in mice from an N-ethyl-N- nitrosoureamutagenesisprogramme.Weidentifiedamousewithautosomaldominanthypercalciuria(HCALC1).Linkage studiesmappedtheHcalc1locustoa11.94Mbregiononchromosome6containingthetransientreceptorpotentialcation 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 (Trpv5682P