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

Martin Krahn (1) , Christophe Béroud (2) , Véronique Labelle (3) , Karine Nguyen (4) , Rafaelle Bernard (1) , Guillaume Bassez (5) , Dominique Figarella-Branger (6) , Carla Fernandez (6) , Julien Bouvenot (7) , Isabelle Richard (8) , Elisabeth Ollagnon-Roman (9) , Jorge A Bevilacqua (10, 11) , Eric Salvo (4) , Shahram Attarian (1) , Françoise Chapon (12) , Jean Pellissier (13) , Jean Pouget (1) , El Hadi Hammouda (14) , Pascal Laforet (5) , Jon Andoni Urtizberea , Bruno Eymard (5) , France Leturcq (15) , Nicolas Lévy (16)

1 GMGF - Génétique Médicale et Génomique Fonctionnelle
2 LGMR - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques
3 APHM - Assistance Publique - Hôpitaux de Marseille
4 Département de génétique médicale [Hôpital de la Timone - APHM]
5 Institut de Myologie
6 Service de pathologie et neuropathologie
7 AMU - Aix Marseille Université
8 CRATG - Centre de recherche et d'applications sur les thérapies géniques
9 Hôpital de la Croix-Rousse [CHU - HCL]
10 Instituto de Ciencias Biomédicas Facultad de Medicina
11 Departamento de Neurología y Neurocirugía [Santiago]
12 Hôpital Côte de Nacre [CHU Caen]
13 Laboratoire d'Anatomopathologie [Aix-Marseille]
14 AFM-Téléthon - Association française contre les myopathies
15 Service de biochimie et de génétique moléculaire [CHU Cochin]
16 ISREC NCCR

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.

Domaines: Bio-informatique [q-bio.QM]; Génétique humaine

Martin Krahn, Christophe Béroud, Véronique Labelle, Karine Nguyen, Rafaelle Bernard, et al.. Analysis of the DYSF mutational spectrum in a large cohort of patients. Human Mutation, 2009, 30 (2), pp.E345 - E375. ⟨10.1002/humu.20910⟩. ⟨hal-01681841⟩