title: A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis.
abstract: Focal and segmental glomerulosclerosis (FSGS) is a kidney disorder of unknown etiology, and up to 20% of patients on dialysis have been diagnosed with it. Here we show that a large family with hereditary FSGS carries a missense mutation in the TRPC6 gene on chromosome 11q, encoding the ion-channel protein transient receptor potential cation channel 6 (TRPC6). The proline-to-glutamine substitution at position 112, which occurs in a highly conserved region of the protein, enhances TRPC6-mediated calcium signals in response to agonists such as angiotensin II and appears to alter the intracellular distribution of TRPC6 protein. Previous work has emphasized the importance of cytoskeletal and structural proteins in proteinuric kidney diseases. Our findings suggest an alternative mechanism for the pathogenesis of glomerular disease.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. michelle.winn@duke.edu
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Winn
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Conlon
authors.forename: Kelvin L
authors.initials: KL
authors.lastname: Lynn
authors.forename: Merry Kay
authors.initials: MK
authors.lastname: Farrington
authors.forename: Tony
authors.initials: T
authors.lastname: Creazzo
authors.forename: April F
authors.initials: AF
authors.lastname: Hawkins
authors.forename: Nikki
authors.initials: N
authors.lastname: Daskalakis
authors.forename: Shu Ying
authors.initials: SY
authors.lastname: Kwan
authors.forename: Seth
authors.initials: S
authors.lastname: Ebersviller
authors.forename: James L
authors.initials: JL
authors.lastname: Burchette
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: David N
authors.initials: DN
authors.lastname: Howell
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Vance
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rosenberg
mesh_terms: D019943:Amino Acid Substitution; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D005091:Exons; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D010375:Pedigree; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D012964:Sodium / Q000378:metabolism; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; D014162:Transfection; D014544:Uridine Triphosphate / Q000378:metabolism / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D044140:Receptor, Angiotensin, Type 1; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D000804:Angiotensin II; D002217:Carbachol; D012964:Sodium; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium; D014544:Uridine Triphosphate