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Am J Transplant. 2015 Dec;15(12):3229-38. doi: 10.1111/ajt.13378. Epub 2015 Jul 3.

Genetic Interactions Between TRPC6 and NPHS1 Variants Affect Posttransplant Risk of Recurrent Focal Segmental Glomerulosclerosis.

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Department of Pediatrics, National University of Singapore, Singapore, Singapore.
Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore, Singapore.
Department of Research, National Neuroscience Institute, Singapore, Singapore.
Department of Physiology, National University of Singapore, Singapore, Singapore.
Department of Pathology, Singapore General Hospital, Singapore, Singapore.
Biostatistics Unit, National University of Singapore, Singapore, Singapore.
Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
David Geffen School of Medicine at UCLA, Los Angeles, CA.
Cedars-Sinai Medical Center, Los Angeles, CA.


Individuals with TRPC6 mutations have variable phenotypes, ranging from healthy carrier to focal segmental glomerulosclerosis (FSGS) leading to renal failure. Here, we describe a family where six members had a novel TRPC6 p.R68W (c.202C>T) mutation, two of whom had renal failure from FSGS, and one had proteinuria. One healthy carrier donated a kidney to her sister. Both donor and recipient had no proteinuria at 20 years posttransplant. Two synonymous NPHS1 polymorphisms, rs2285450 (c.294C>T) and rs437168 (c.2289C>T) segregated with renal failure in this family. These variants had higher allele frequencies in 97 unrelated patients with nephrotic syndrome or FSGS compared to 224 controls. Using patch-clamp experiments in HEK293 and podocytes, we showed that the p.R68W mutation increased TRPC6 current amplitudes, which may be explained by enhanced TRPC6 surface expression. Additionally, while wild-type nephrin suppressed TRPC6 currents, this ability was lost in the presence of NPHS1 c.294C>T polymorphism. When cells were transfected according to combined TRPC6 and NPHS1 genotypes in the family, those representing the donor had lower TRPC6 currents than cells representing the recipient, suggesting that interactions between TRPC6 and NPHS1 variants could possibly account for the variable penetrance of TRPC6 mutations and the absence of recurrence in the graft.

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