Analysis of the DYSF mutational spectrum in a large cohort of patients.
Dysferlinopathies belong to the heterogeneous group of autosomal recessive muscular dystrophies. Mutations in the gene encoding dysferlin (DYSF) lead to distinct phenotypes, mainly Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). Here, we analysed the mutational data from the largest cohort described to date, a cohort of 134 patients, included based on clinical suspicion of primary dysferlinopathy and/or dysferlin protein deficiency identified on muscle biopsy samples. Data were compiled from 38 patients previously screened for mutations in our laboratory (Nguyen, et al., 2005; Nguyen, et al., 2007), and 96 supplementary patients screened for DYSF mutations using genomic DHPLC analysis, and subsequent sequencing of detected variants, in a routine diagnostic setting. In 89 (66%) out of 134 patients, molecular analysis identified two disease causing mutations, confirming the diagnosis of primary Dysferlinopathy on a genetic basis. Furthermore, one mutation was identified in 30 patients, without identification of a second deleterious allele. We are currently developing complementary analysis for patients in whom only one or no disease-causing allele could be identified using the genomic screening procedure. Altogether, 64 novel mutations have been identified in this cohort, which corresponds to approximately 25% of all DYSF mutations reported to date. The mutational spectrum of this cohort significantly shows a higher proportion of nonsense mutations, but a lower proportion of deleterious missense changes as compared to previous series. (c) 2008 Wiley-Liss, Inc.
Département de Génétique Médicale, Hôpital d'Enfants de la Timone, AP-HM, Marseille, France.
Martin
M
Krahn
Christophe
C
Béroud
Véronique
V
Labelle
Karine
K
Nguyen
Rafaëlle
R
Bernard
Guillaume
G
Bassez
Dominique
D
Figarella-Branger
Carla
C
Fernandez
Julien
J
Bouvenot
Isabelle
I
Richard
Elisabeth
E
Ollagnon-Roman
Jorge A
JA
Bevilacqua
Eric
E
Salvo
Shahram
S
Attarian
Françoise
F
Chapon
Jean-François
JF
Pellissier
Jean
J
Pouget
El Hadi
el H
Hammouda
Pascal
P
Laforêt
Jon Andoni
JA
Urtizberea
Bruno
B
Eymard
France
F
Leturcq
Nicolas
N
Lévy
D000293:Adolescent; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D000073939:Dysferlin; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D009136:Muscular Dystrophies / Q000175:diagnosis / Q000235:genetics; D009154:Mutation / Q000235:genetics*
C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins