@misc{batool_an_inactivating_2023, 
author={Batool, L.,Hariharan, K.,Xu, Y.,Kaßmann, M.,Tsvetkov, D.,Gohlke, B.O.,Kaden, S.,Gossen, M.,Nürnberg, B.,Kurtz, A.,Gollasch, M.},
title={An inactivating human TRPC6 channel mutation without focal segmental glomerulosclerosis},
year={2023},
howpublished = {journal article},
doi = {https://doi.org/10.1007/s00018-023-04901-w},
abstract = {Transient receptor potential cation channel-6 (TRPC6) gene mutations cause familial focal segmental glomerulosclerosis (FSGS), which is inherited as an autosomal dominant disease. In patients with TRPC6-related FSGS, all mutations map to the N- or C-terminal TRPC6 protein domains. Thus far, the majority of TRPC6 mutations are missense resulting in increased or decreased calcium influx; however, the fundamental molecular mechanisms causing cell injury and kidney pathology are unclear. We report a novel heterozygous TRPC6 mutation (V691Kfs*) in a large kindred with no signs of FSGS despite a largely truncated TRPC6 protein. We studied the molecular effects of V691Kfs* TRPC6 mutant using the tridimensional cryo-EM structure of the tetrameric TRPC6 protein. The results indicated that V691 is localized at the pore-forming transmembrane region affecting the ion conduction pathway, and predicted that V691Kfs* causes closure of the ion-conducting pathway leading to channel inactivation. We assessed the impact of V691Kfs* and two previously reported TRPC6 disease mutants (P112Q and G757D) on calcium influx in cells. Our data show that the V691Kfs* fully inactivated the TRCP6 channel-specific calcium influx consistent with a complete loss-of-function phenotype. Furthermore, the V691Kfs* truncation exerted a dominant negative effect on the full-length TRPC6 proteins. In conclusion, the V691Kfs* non-functional truncated TRPC6 is not sufficient to cause FSGS. Our data corroborate recently characterized TRPC6 loss-of-function and gain-of-function mutants suggesting that one defective TRPC6 gene copy is not sufficient to cause FSGS. We underscore the importance of increased rather than reduced calcium influx through TRPC6 for podocyte cell death.},
note = {Online available at: \url{https://doi.org/10.1007/s00018-023-04901-w} (DOI). Batool, L.; Hariharan, K.; Xu, Y.; Kaßmann, M.; Tsvetkov, D.; Gohlke, B.; Kaden, S.; Gossen, M.; Nürnberg, B.; Kurtz, A.; Gollasch, M.: An inactivating human TRPC6 channel mutation without focal segmental glomerulosclerosis. Cellular and Molecular Life Sciences. 2023. vol. 80, no. 9, 256. DOI: 10.1007/s00018-023-04901-w}}