A novel TRPC6 mutation that causes childhood FSGS.
Saskia F Heeringa1, Clemens C Möller, Jianyang Du
1Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, United States of America.
Plos One
|November 26, 2009
Summary
A novel mutation in the TRPC6 gene (M132T) causes early-onset focal segmental glomerulosclerosis (FSGS) in children. This mutation significantly increases TRPC6 channel activity, leading to a more aggressive form of FSGS.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Transient receptor potential cation channel subfamily member 6 (TRPC6) mutations are linked to autosomal-dominant focal segmental glomerulosclerosis (FSGS).
- Seven TRPC6 mutations are known to cause FSGS in adults.
Purpose of the Study:
- To identify novel mutations in TRPC6 causing early-onset FSGS.
- To characterize the functional consequences of a newly identified TRPC6 mutation (M132T).
Main Methods:
- Screened 550 families with steroid-resistant nephrotic syndrome (SRNS) for autosomal-dominant FSGS.
- Performed whole-cell current recordings on wild-type and mutant TRPC6 channels.
- Analyzed TRPC6 mutation segregation in affected pedigrees.
Main Results:
- Identified a novel TRPC6 mutation (M132T) segregating with early-onset FSGS in pediatric individuals.
- The M132T mutation increased TRPC6 channel current amplitude 3-5 fold and inward calcium current 10-fold.
- M132T TRPC6 mutants exhibited a lack of time-dependent inactivation.
Conclusions:
- TRPC6-mediated FSGS can occur in children.
- The M132T TRPC6 mutation leads to an aggressive FSGS phenotype due to increased channel activity and impaired inactivation.
- Calcium flux through TRPC6 is critical in the pathogenesis of FSGS.
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