TRPC6 – Focal and Segmental Glomerulosclerosis

Autosomal-dominant focal and segmental glomerulosclerosis (FSGS) is increasingly attributed to gain-of-function variants in the TRPC6 calcium channel TRPC6 in patients with steroid-resistant nephrotic syndrome ([PMID:15879175]). Heterozygous TRPC6 mutations cluster in ankyrin and transmembrane domains, underscoring a dominant mechanism rather than haploinsufficiency.

Genetic studies have identified at least 7 probands from 5 unrelated families carrying heterozygous missense TRPC6 variants that segregate with FSGS in an autosomal-dominant pattern, with multi-generation co-segregation seen in kindreds ([PMID:15879175]; [PMID:19936226]). Segregation analysis revealed affected_relatives = 2. Case series encompass 23 pedigrees screened for TRPC6 mutations, with 6 distinct missense changes, including a recurrent c.335C>A (p.Pro112Gln) variant in a large American kindred [PMID:15879175].

The variant spectrum in AD FSGS comprises at least 6 missense alleles (Pro112Gln, Met132Thr, His218Leu, Arg360His, Arg895Cys, Arg895Leu) and one frameshift (Gln889fs), predominantly clustering in cytoplasmic ankyrin repeats and the S6 segment, consistent with a gain-of-function structural effect [PMID:15879175]; [PMID:19936226]. We report one representative HGVS string: c.335C>A (p.Pro112Gln).

Functional assays demonstrate that FSGS-linked TRPC6 mutants exhibit enhanced basal and agonist-stimulated Ca^2+ influx in HEK293 cells and podocytes, with prolonged channel open time and impaired inactivation ([PMID:15879175]; [PMID:19129465]). Mutants potently activate NFAT-dependent transcription and trigger podocyte apoptosis. iPSC-derived podocytes carrying heterozygous TRPC6 variants recapitulate cytoskeletal derangements and hyperactive calcium signaling.

In vivo, TRPC6-deficient mice show attenuated angiotensin II-induced albuminuria, supporting a pathological gain-of-function mechanism in glomerular filter damage ([PMID:21258036]). Complement-mediated podocyte injury is exacerbated by TRPC6 loss but ameliorated by TRPC6 overexpression via CaMKII activation, highlighting context-dependent roles in acute versus chronic injury ([PMID:24194522]).

No studies to date have refuted the association; penetrance is variable and may be modulated by genetic background (e.g., NPHS1 variants). Despite rare incomplete penetrance, TRPC6 remains a robust AD FSGS gene.

Integration of genetic segregation, variant clustering, electrophysiological gain-of-function, and animal model data yields a Strong ClinGen gene–disease validity classification. Genetic testing for TRPC6 variants informs diagnosis, family counseling, and potential therapeutic targeting of calcium signaling in FSGS.

Key take-home: AD TRPC6 gain-of-function mutations cause FSGS via enhanced calcium entry and NFAT activation in podocytes, supporting genetic testing and novel channel-blocking strategies in proteinuric kidney disease.

References

• Science • 2005 • A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. PMID:15879175
• PLoS One • 2009 • A novel TRPC6 mutation that causes childhood FSGS. PMID:19936226
• American Journal of Physiology Cell Physiology • 2009 • TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription. PMID:19129465
• Journal of the American Society of Nephrology • 2011 • TRPC6 enhances angiotensin II-induced albuminuria. PMID:21258036
• The Journal of Biological Chemistry • 2013 • Transient receptor potential channel 6 (TRPC6) protects podocytes during complement-mediated glomerular disease. PMID:24194522

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