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An inactivating human TRPC6 channel mutation without focal segmental glomerulosclerosis
Lilas Batool1, Krithika Hariharan1,2, Yao Xu3
1BIH Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
Cellular and Molecular Life Sciences : CMLS
|August 24, 2023
Summary
A novel mutation in the Transient Receptor Potential Cation Channel-6 (TRPC6) gene, V691Kfs*, caused a loss-of-function but did not lead to familial focal segmental glomerulosclerosis (FSGS). This suggests TRPC6 loss-of-function is not sufficient to cause FSGS.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Familial focal segmental glomerulosclerosis (FSGS) is an inherited kidney disease often caused by mutations in the Transient Receptor Potential Cation Channel-6 (TRPC6) gene.
- Most known TRPC6 mutations are missense, leading to altered calcium influx, but the precise mechanisms of kidney pathology remain unclear.
Purpose of the Study:
- To investigate the molecular effects of a novel heterozygous TRPC6 mutation (V691Kfs*) identified in a large kindred without FSGS.
- To determine if this loss-of-function mutation is sufficient to cause FSGS and to explore its impact on TRPC6 channel activity and protein interactions.
Main Methods:
- Utilized the tridimensional cryo-electron microscopy (cryo-EM) structure of the tetrameric TRPC6 protein to analyze the V691Kfs* mutation's location and predicted effect.
- Assessed the impact of the V691Kfs* mutant, alongside previously reported mutants (P112Q, G757D), on calcium influx in cellular models.
- Evaluated the dominant-negative effect of the V691Kfs* truncation on full-length TRPC6 proteins.
Main Results:
- The V691Kfs* mutation localizes to the pore-forming transmembrane region, predicted to cause channel inactivation and a complete loss-of-function phenotype by closing the ion-conducting pathway.
- Cellular assays confirmed that V691Kfs* fully inactivated TRPC6-specific calcium influx.
- The V691Kfs* truncated TRPC6 protein exhibited a dominant-negative effect on wild-type TRPC6 proteins.
Conclusions:
- The non-functional, truncated TRPC6 protein resulting from the V691Kfs* mutation is insufficient to cause FSGS.
- These findings support recent studies indicating that both loss-of-function and gain-of-function TRPC6 mutations require specific conditions or interactions, and a single defective copy may not be enough to trigger FSGS.
- The study underscores that increased, rather than reduced, calcium influx through TRPC6 is critical for podocyte injury and the development of FSGS.
