title: TRPV5 gene polymorphisms in renal hypercalciuria.
abstract: BACKGROUND
  Kidney stone formation is a major socioeconomic problem in humans, involving pain, recurrent treatment and renal insufficiency. As most renal precipitates contain calcium as a major component, hypercalciuria is the main risk factor for renal stone formation. Different forms of hypercalciuria can be classified, which primarily arise from defects in the main organs involved in calcium homeostasis. A distinction can be made between renal, absorptive and resorptive hypercalciuria, originating from disturbed calcium handling in kidney, intestine and bone, respectively. A positive family history predisposes individuals to an increased risk of stone formation, which strongly indicates the involvement of genetic susceptibility factors. TRPV5 is the renal epithelial calcium channel that is the gatekeeper protein in active calcium reabsorption in the kidney. TRPV5 gene ablation in mice leads to severe hypercalciuria, implying that TRPV5 is an interesting candidate gene for renal hypercalciuria in humans. This study aims to identify and functionally characterize TRPV5 gene aberrations in patients with renal hypercalciuria.
  
  
  METHODS
  The TRPV5 coding region and intron-exon boundaries were screened for gene mutations in 20 subjects displaying renal hypercalciuria after which identified non-synonymous polymorphisms were functionally characterized by patch-clamp analysis. Wild-type and TRPV5 channels including polymorphisms were transiently expressed in human embryonic kidney (HEK) 293 cells and functionally characterized by path-clamp analysis.
  
  
  RESULTS
  Genotyping TRPV5 in renal hypercalciuria patients revealed three non-synonymous and five synonymous polymorphisms. Electrophysiological characterization of the TRPV5 mutants did not reveal significant functional changes compared to wild-type TRPV5 channel recordings.
  
  
  CONCLUSIONS
  In this specific patient cohort, our data do not support a primary role for TRPV5 in the pathogenesis of renal hypercalciuria. However, TRPV5 cannot be excluded as a candidate gene in hypercalciuria.
authors.affiliation: Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, The Netherlands.
authors.forename: Kirsten Y
authors.initials: KY
authors.lastname: Renkema
authors.forename: Kyupil
authors.initials: K
authors.lastname: Lee
authors.forename: Catalin N
authors.initials: CN
authors.lastname: Topala
authors.forename: Monique
authors.initials: M
authors.lastname: Goossens
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.forename: René J
authors.initials: RJ
authors.lastname: Bindels
authors.forename: Joost G
authors.initials: JG
authors.lastname: Hoenderop
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D015331:Cohort Studies; D017931:DNA Primers / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D053565:Hypercalciuria / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D007669:Kidney Calculi / Q000209:etiology / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D017931:DNA Primers; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C492239:TRPV5 protein, human