A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis.
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.
Winn
Michelle P
MP
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. michelle.winn@duke.edu
Conlon
Peter J
PJ
Lynn
Kelvin L
KL
Farrington
Merry Kay
MK
Creazzo
Tony
T
Hawkins
April F
AF
Daskalakis
Nikki
N
Kwan
Shu Ying
SY
Ebersviller
Seth
S
Burchette
James L
JL
Pericak-Vance
Margaret A
MA
Howell
David N
DN
Vance
Jeffery M
JM
Rosenberg
Paul B
PB
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
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