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.
Krahn
Martin
M
Département de Génétique Médicale, Hôpital d'Enfants de la Timone, AP-HM, Marseille, France.
Béroud
Christophe
C
Labelle
Véronique
V
Nguyen
Karine
K
Bernard
Rafaëlle
R
Bassez
Guillaume
G
Figarella-Branger
Dominique
D
Fernandez
Carla
C
Bouvenot
Julien
J
Richard
Isabelle
I
Ollagnon-Roman
Elisabeth
E
Bevilacqua
Jorge A
JA
Salvo
Eric
E
Attarian
Shahram
S
Chapon
Françoise
F
Pellissier
Jean-François
JF
Pouget
Jean
J
Hammouda
El Hadi
el H
Laforêt
Pascal
P
Urtizberea
Jon Andoni
JA
Eymard
Bruno
B
Leturcq
France
F
Lévy
Nicolas
N
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