Analysis of the DYSF mutational spectrum in a large cohort of patients.

Abstract

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.

• Authors: Martin Krahn, Christophe Béroud, Véronique Labelle, Karine Nguyen, Rafaëlle Bernard, Guillaume Bassez, Dominique Figarella-Branger, Carla Fernandez, Julien Bouvenot, Isabelle Richard, Elisabeth Ollagnon-Roman, Jorge A Bevilacqua, Eric Salvo, Shahram Attarian, Françoise Chapon, Jean-François Pellissier, Jean Pouget, El Hadi Hammouda, Pascal Laforêt, Jon Andoni Urtizberea, Bruno Eymard, France Leturcq, Nicolas Lévy
• Journal: Human mutation (Hum Mutat) Vol. 30 Issue 2 Pg. E345-75 (Feb 2009) ISSN: 1098-1004 [Electronic] United States
• PMID: 18853459 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2008 Wiley-Liss, Inc.

Chemical References

• DYSF protein, human
• Dysferlin
• Membrane Proteins
• Muscle Proteins

Topics

• Adolescent
• Adult
• Aged
• Cohort Studies
• DNA Mutational Analysis
• Dysferlin
• Female
• Humans
• Male
• Membrane Proteins (genetics)
• Middle Aged
• Muscle Proteins (genetics)
• Muscular Dystrophies (diagnosis, genetics)
• Mutation (genetics)