Abstract: TH-PO498
Clinical and Genetic Assessment for the Mechanisms Underlying Phenotypic Diversity in Steroid-Resistant Nephrotic Syndrome Caused by TRPC6 Variants
Session Information
- Genetic Kidney Diseases: Genotypes and Phenotypes in Cases
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Tsukaguchi, Hiroyasu, Kansai Medical University, Second Department of Internal Medicine, Hirakata, Osaka, Japan
- Tran Thuy, Huong Quynh, Kansai Medical University, Second Department of Internal Medicine, Hirakata, Osaka, Japan
- Hayashi, Mikio, Kansai Medical University, Department of Physiology, Hirakata, Osaka, Japan
- Fukui, Kenji, Osaka Medical and Pharmaceutical University, Faculty of Medicine, Department of Biochemistry, Takatsuki, Osaka, Japan
Group or Team Name
- Div of Nephrology.
Background
Histologically, 30% of children and 10% of adult individuals with steroid resistant nephrotic syndrome (SRNS) are characterized by Focal Segmental Glomerulosclerosis (FSGS). More than 60 podocyte-related gene mutations have been reported in monogenic SRNS. Among these, TRPC6 variants account for approximately 6% of familial FSGS and 2% in sporadic cases. Individuals with TRPC6 variants show a considerable clinical diversity with regards to age onset and disease progression. However, the mechanisms underlying the heterogeneity remain investigated.
Methods
To analyzing the molecular basis of TRPC6 glomerulopathy, we investigated the clinical-genetic features of TRPC6 variants in our SRNS cohort (n=39, average onset of proteinuria 4.6 years, ESRD 7.6 years)
Results
Genetic analysis revealed TRPC6 variant is the most frequent cause of SRNS (n=8, 21%), followed by NUP107 (n=5), PLCE1(n=3), COL4A3,A5(n=2). The eight TRPC6 variants remarkably clustered into two distinctive cytoplasmic domains: Four in the N-terminal Ankyrin repeat 3 (AR3 163-189 (p.Y173D, R175W, R175G) and the other four C-terminal helix (CH1 and CH2 853-920, p.E875V, 867_868Del, S893N, R895C). Three patients exhibited NS in early childhood around age 3, two manifested in childhood (age 3-12), while the remaining 3 developed NS in adolescence. In familial cases, for example, affected individuals with p.R175W or p.R875V showed discordant age onset and disease severity. The 3D structure analysis with the homo-tetrameric TRPC6 complex revealed that all pathogenic TRPC6 variants alter the residues composing Ca-permeable pore in the center of the protein complex. Expression studies with HEK293 cells showed that TRPC6 variants are expressed on the cell surface, supporting that an excessive Ca influx through the gain-of-function of channel may contribute to the podocyte injury.
Conclusion
TRPC6 channelopathy was found to be the most frequent cause in our SRNS cohort. The pathogenic variants likely disrupt the integrity of AR3-CH2 interface, which confers a Ca-binding site for channel inactivation. Remarkable clinical heterogeneity suggests that channel activity may be regulated by other modifying factors. Further studies will be required to address how the excessive Ca influx affect the cytoskeletal organization in the podocytes.