TRPC6 Mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype

Maddalena Gigante, Gianluca Caridi, Eustacchio Montemurno, Mario Soccio, Maria D'Apolito, Giuseppina Cerullo, Filippo Aucella, Annalisa Schirinzi, Francesco Emma, Laura Massella, Giovanni Messina, Tommaso de Palo, Elena Ranieri, Gian Marco Ghiggeri, Loreto Gesualdo

Research output: Contribution to journalArticlepeer-review


Background and objectives Mutations in the TRPC6 gene have been recently identified as the cause of lateonset autosomal-dominant focal segmental glomerulosclerosis (FSGS). To extend the screening, we analyzed TRPC6 in 33 Italian children with sporadic early-onset SRNS and three Italian families with adult-onset FSGS. Design, setting, participants, & measurements TRPC6 mutation analysis was performed through PCR and sequencing. The effects of the detected amino acid substitutions were analyzed by bioinformatics tools and functional in vitro studies. The expression levels of TRPC6 and nephrin proteins were evaluated by confocal microscopy. Results Three heterozygous missense mutations (c.374A>G_p.N125S, c.653A>T_p.H218L, c.2684G>T_p.R895L) were identified. The first new mutation, p.H218L, was found in a 18-year-old boy who presented a severe form of FSGS at the age of 8 years. The second, p.R895L, a new de novo mutation, was identified in a girl with collapsing glomerulosclerosis at the age of 2 years. The former mutation, p.N125S, was found in two siblings with early-onset steroid-resistant nephrotic syndrome (SRNS) at the ages of 4 and 14 years. Renal immunofluorescence revealed upregulated expression of TRPC6 and loss of nephrin in glomeruli. The intracellular calcium concentrations were significantly higher in the cells expressing all mutant TRPC6 channels compared with cells expressing wild-type TRPC6. Conclusions Our findings suggest that TRPC6 variants can also be detected in children with early-onset and sporadic SRNS (4 of 33 patients). Moreover, in one patient a new de novo TRPC6 mutation was associated with a rare severe form of childhood collapsing glomerulosclerosis with rapid progression to uremia.

Original languageEnglish
Pages (from-to)1626-1634
Number of pages9
JournalClinical Journal of the American Society of Nephrology
Issue number7
Publication statusPublished - Jul 1 2011

ASJC Scopus subject areas

  • Nephrology
  • Transplantation
  • Epidemiology
  • Critical Care and Intensive Care Medicine


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