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


METHODS
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.
Vilchez
Juan J
JJ
Servicio de Neurología, Hospital Universitari La Fe, Valencia, Spain.
Gallano
Pia
P
Gallardo
Eduard
E
Lasa
Adriana
A
Rojas-García
Ricardo
R
Freixas
Alba
A
De Luna
Noemí
N
Calafell
Francesc
F
Sevilla
Teresa
T
Mayordomo
Fernando
F
Baiget
Montserrat
M
Illa
Isabel
I
D000293:Adolescent; D000328:Adult; D018389:Codon, Nonsense / Q000235:genetics; D004252:DNA Mutational Analysis; D000073939:Dysferlin; D005260:Female; D018703:Founder Effect; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D009136:Muscular Dystrophies / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D013030:Spain
D018389:Codon, Nonsense; C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins