TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis

Background. Mutations in the TRPC6 gene have been re- ported in six families with adult-onset (17-57 years) autoso- mal dominant focal segmental glomerulosclerosis (FSGS). Electrophysiology studies confirmed augmented calcium influx only in three of these six TRPC6 mutations. To date, the role of TRPC6 in childhood and adulthood non-familial forms is unknown. Methods. TRPC6 mutation analysis was performed by di- rect sequencing in 130 Spanish patients from 115 unre- lated families with FSGS. An in silico scoring matrix was developed to evaluate the pathogenicity of amino acid substitutions, by using the bio-physical and bio-chemical differences between wild-type and mutant amino acid, the evolutionary conservation of the amino acid residue in orthologues, homologues and defined domains, with the addition of contextual information. Results. Three new missense substitutions were identified in two clinically non-familial cases and in one familial case. The analysis by means of this scoring system allowed us to classify these variants as likely pathogenic mutations. One of them was detected in a female patient with unusual clin- ical features: mesangial proliferative FSGS in childhood (7 years) and partial response to immunosupressive ther- apy (CsA + MMF). Asymptomatic carriers of this likely mutation were found within her family. Conclusions. We describe for the first time TRPC6 mu- tations in children and adults with non-familial FSGS. It seems that TRPC6 is a gene with a very variable penetrance that may contribute to glomerular diseases in a multi-hit setting.