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NDT Advance Access originally published online on May 20, 2009
Nephrology Dialysis Transplantation 2009 24(10):3089-3096; doi:10.1093/ndt/gfp229
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© The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


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

Sheila Santín1, Elisabet Ars1, Sandro Rossetti2, Eduardo Salido3, Irene Silva1, Rafael García-Maset4, Isabel Giménez4, Patricia Ruíz1, Santiago Mendizábal5, José Luciano Nieto6, Antonia Peña7, Juan Antonio Camacho8, Gloria Fraga9, Mª Ángeles Cobo10, Carmen Bernis11, Alberto Ortiz12, Augusto Luque de Pablos13, Ana Sánchez-Moreno14, Guillem Pintos15, Eduard Mirapeix16, Patricia Fernández-Llama4, José Ballarín4, Roser Torra4 and on behalf of the FSGS Study Group*

1 Molecular Biology Laboratory, Fundació Puigvert, Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain 2 Division of Nephrology and Hypertension, College of Medicine, Mayo Clinic, Rochester, MN, USA 3 Molecular Biology Laboratory, Hospital Universitario de Canarias, Tenerife 4 Nephrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona 5 Pediatric Nephrology Department, Hospital Universitario La Fe, Valencia 6 Pediatric Nephrology Department, Hospital Vall d’Hebron, Barcelona 7 Pediatric Nephrology Department, Hospital Infantil La Paz, Madrid 8 Pediatric Nephrology Department, Hospital Sant Joan de Déu, Barcelona 9 Pediatric Nephrology Department, Hospital de la Santa Creu i Sant Pau, Barcelona 10 Nephrology Department, Hospital Universitario de Canarias, Tenerife 11 Nephrology Department, Hospital Universitario de La Princesa, Madrid 12 Nephrology Department, Fundación Jiménez Díaz, Madrid 13 Pediatric Nephrology Department, Hospital General Universitario Gregorio Marañón, Madrid 14 Pediatric Nephrology Department, Hospital Infantil Universitario Virgen del Rocío, Sevilla 15 Pediatric Nephrology Department, Hospital Germans Trias i Pujol, Badalona 16 Nephrology Department, Hospital Clinic, Barcelona, Spain

Correspondence and offprint requests to: Roser Torra; E-mail: rtorra{at}fundacio-puigvert.es



  Abstract

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.

Keywords: focal segmental glomerulosclerosis; in silico scoring system; missense substitutions; mutation analysis; TRPC6 gene

* Other investigators in the FSGS Study Group are listed below: Hospital Universitario La Fe- Isabel Zamora; Hospital Vall d’Hebron- Joan López-Hellin, Álvaro Madrid, Clara Ventura, Ramón Vilalta; Hospital Infantil La Paz- Laura Espinosa, Carmen García, Marta Melgosa, Mercedes Navarro; Hospital Sant Joan de Déu- Antonio Giménez, Jorge Vila Cots; Fundación Jiménez Díaz- Simona Alexandra, Carlos Caramelo{dagger}, Jesús Egido; Hospital General Universitario Gregorio Marañón- M Dolores Morales San José; Hospital Infantil Universitario Virgen del Rocío- Francisco de la Cerda; Hospital de Barcelona- Pere Sala, Frederic Raspall, Ángel Vila; Hospital Torrecárdenas- Antonio María Daza; Hospital Niño Jesús- Mercedes Vázquez, José Luis Écija; Hospital Universitario Reina Sofía- Mario Espinosa; Hospital Infantil Miguel Servet- Ma Luisa Justa; Hospital Princeps d’España- Rafael Poveda; Hospital Universitario de Getafe- Cristina Aparicio; Hospital Materno-Infantil Son Dureta- Jordi Rosell; Hospital Infantil doce de Octubre- Rafael Muley; Hospital de Galdakao- Jesús Montenegro; Hospital Universitario Marqués de Valdecilla- Domingo González; Hospital Materno-Infantil de Badajoz- Emilia Hidalgo; Hospital Universitario Virgen de las Nieves- David Barajas de Frutos; Hospital Son Llàtzer- Esther Trillo; Hospital Universitario Virgen de la Arrixaca- Salvador Gracia; Hospital de Cruces- Francisco Javier Gainza de los Ríos.

Received for publication: 12. 1.09
Accepted in revised form: 27. 4.09


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