Identification of a novel founder mutation in the DYSF gene causing clinical variability in the spanish population

Juan J. Vilchez, Pia Gallano, Eduard Gallardo, Adriana Lasa, Ricardo Rojas-García, Alba Freixas, Noemí De Luna, Francesc Calafell, Teresa Sevilla, Fernando Mayordomo, Montserrat Baiget, Isabel Illa

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Background: Mutations in the dysferlin (DYSF) gene cause 3 different phenotypes of muscular dystrophies: Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal anterior compartment myopathy. Objective: To present the results of clinical and molecular analysis of 8 patients with dysferlinopathy from 5 unrelated families. Design: Clinical assessment was performed with a standardized protocol. A muscle biopsy specimen was obtained and studied by immunohistochemistry. Genetic analysis was performed using single-stranded conformation polymorphism and direct sequencing of genomic DNA. Results: All the patients presented the R1905X mutation in the DYSF gene in homozygosity, and the haplotype analysis at the DYSF locus revealed that it was a novel and founder mutation. A C-to-T transition at nucleotide position 6086 changes an arginine into a stop codon, leading to premature termination of translation. This mutation was expressed as 3 different clinical phenotypes (limb-girdle muscular dystrophy type 2B, Miyoshi distal myopathy, and distal anterior dysferlinopathy), but only 1 phenotype was found in the same family. Conclusions: The new R1905X DYSF founder mutation produced the 3 possible dysferlinopathy phenotypes without intrafamilial heterogeneity. This homogeneous population in Sueca, Spain, should be helpful in studying the modifying factors responsible for the phenotypic variability. ©2005 American Medical Association. All rights reserved.
Idioma originalEnglish
Pàgines (de-a)1256-1259
RevistaArchives of Neurology
Estat de la publicacióPublicada - 1 d’ag. 2005


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