TY - JOUR
T1 - TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis
AU - Santín, Sheila
AU - Ars, Elisabet
AU - Rossetti, Sandro
AU - Salido, Eduardo
AU - Silva, Irene
AU - García-Maset, Rafael
AU - Giménez, Isabel
AU - Ruíz, Patricia
AU - Mendizábal, Santiago
AU - Nieto, José Luciano
AU - Peña, Antonia
AU - Camacho, Juan Antonio
AU - Fraga, Gloria
AU - Cobo, M. Ángeles
AU - Bernis, Carmen
AU - Ortiz, Alberto
AU - De Pablos, Augusto Luque
AU - Sánchez-Moreno, Ana
AU - Pintos, Guillem
AU - Mirapeix, Eduard
AU - Fernández-Llama, Patricia
AU - Ballarín, José
AU - Torra, Roser
PY - 2009/10/1
Y1 - 2009/10/1
N2 - Background. Mutations in the TRPC6 gene have been reported in six families with adult-onset (17-57 years) autosomal 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 direct sequencing in 130 Spanish patients from 115 unrelated 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 clinical features: mesangial proliferative FSGS in childhood (7 years) and partial response to immunosupressive therapy (CsA + MMF). Asymptomatic carriers of this likely mutation were found within her family.Conclusions. We describe for the first time TRPC6 mutations 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.
AB - Background. Mutations in the TRPC6 gene have been reported in six families with adult-onset (17-57 years) autosomal 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 direct sequencing in 130 Spanish patients from 115 unrelated 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 clinical features: mesangial proliferative FSGS in childhood (7 years) and partial response to immunosupressive therapy (CsA + MMF). Asymptomatic carriers of this likely mutation were found within her family.Conclusions. We describe for the first time TRPC6 mutations 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.
KW - Focal segmental glomerulosclerosis
KW - In silico scoring system
KW - Missense substitutions
KW - Mutation analysis
KW - TRPC6 gene
U2 - 10.1093/ndt/gfp229
DO - 10.1093/ndt/gfp229
M3 - Article
VL - 24
SP - 3089
EP - 3096
IS - 10
ER -