TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis.
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.
Santín
Sheila
S
Fundació Puigvert, Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain.
Ars
Elisabet
E
Rossetti
Sandro
S
Salido
Eduardo
E
Silva
Irene
I
García-Maset
Rafael
R
Giménez
Isabel
I
Ruíz
Patricia
P
Mendizábal
Santiago
S
Luciano Nieto
José
J
Peña
Antonia
A
Camacho
Juan Antonio
JA
Fraga
Gloria
G
Cobo
M Angeles
MA
Bernis
Carmen
C
Ortiz
Alberto
A
de Pablos
Augusto Luque
AL
Sánchez-Moreno
Ana
A
Pintos
Guillem
G
Mirapeix
Eduard
E
Fernández-Llama
Patricia
P
Ballarín
José
J
Torra
Roser
R
Zamora
Isabel
I
López-Hellin
Joan
J
Madrid
Alvaro
A
Ventura
Clara
C
Vilalta
Ramón
R
Espinosa
Laura
L
García
Carmen
C
Melgosa
Marta
M
Navarro
Mercedes
M
Giménez
Antonio
A
Cots
Jorge Vila
JV
Alexandra
Simona
S
Caramelo
Carlos
C
Egido
Jesús
J
San José
M Dolores Morales
MD
de la Cerda
Francisco
F
Sala
Pere
P
Raspall
Frederic
F
Vila
Angel
A
Daza
Antonio María
AM
Vázquez
Mercedes
M
Ecija
José Luis
JL
Espinosa
Mario
M
Justa
Ma Luisa
ML
Poveda
Rafael
R
Aparicio
Cristina
C
Rosell
Jordi
J
Muley
Rafael
R
Montenegro
Jesús
J
González
Domingo
D
Hidalgo
Emilia
E
de Frutos
David Barajas
DB
Trillo
Esther
E
Gracia
Salvador
S
de los Ríos
Francisco Javier Gainza
FJ
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D006801:Humans; D007223:Infant; D008875:Middle Aged; D050052:TRPC Cation Channels / Q000235:genetics*; D000074287:TRPC6 Cation Channel; D055815:Young Adult
D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human