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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Substitution
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Angiotensin II / metabolism
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Angiotensin II / pharmacology
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Calcium / metabolism
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Calcium Channels / chemistry
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Calcium Channels / genetics*
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Calcium Channels / metabolism
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Calcium Signaling
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Carbachol / pharmacology
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Cell Line
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Cell Membrane / metabolism
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Chromosomes, Human, Pair 11 / genetics
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Exons
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Female
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GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
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Glomerulosclerosis, Focal Segmental / genetics*
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Haplotypes
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Humans
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Kidney / metabolism
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Kidney Glomerulus / metabolism
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Kidney Tubules / metabolism
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Male
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Mutation, Missense*
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Patch-Clamp Techniques
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Pedigree
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Receptor, Angiotensin, Type 1 / genetics
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Receptor, Angiotensin, Type 1 / metabolism
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Sequence Analysis, DNA
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Sodium / metabolism
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TRPC Cation Channels
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TRPC6 Cation Channel
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Transfection
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Uridine Triphosphate / metabolism
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Uridine Triphosphate / pharmacology
Substances
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Calcium Channels
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Receptor, Angiotensin, Type 1
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TRPC Cation Channels
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TRPC6 Cation Channel
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TRPC6 protein, human
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Angiotensin II
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Carbachol
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Sodium
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GTP-Binding Protein alpha Subunits, Gq-G11
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Calcium
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Uridine Triphosphate