title: Mutation finding in patients with dysferlin deficiency and role of the dysferlin interacting proteins annexin A1 and A2 in muscular dystrophies.
abstract: Mutations in the DYSF gene underlie two main muscle diseases: Limb Girdle Muscular Dystrophy (LGMD) 2B and Miyoshi myopathy (MM). Dysferlin is involved in muscle membrane-repair and is thought to interact with other dysferlin molecules and annexins A1 and A2 at the sarcolemma. We performed genotype/phenotype correlations in a large cohort of dysferlinopathic patients and explored the possible role of annexins as modifier factors in LGMD-2B and MM. In particular, clinical examination, expression of sarcolemmal proteins and genetic analysis were performed on 27 dysferlinopathic subjects. Expression of A1 and A2 annexins was investigated in LGMD-2B/MM subjects and in patients with other muscle disorders. We identified 24 different DYSF mutations, 10 of them being novel. We observed no clear correlation between mutation type and clinical phenotype, but MM patients were found to display muscle symptoms significantly earlier in life than LGMD subjects. Remarkably, dysferlinopathic patients and subjects suffering from other muscular disorders expressed higher levels of both annexins compared to controls; a significant correlation was observed between annexin expression levels and clinical severity scores. Also, annexin amounts paralleled the degree of muscle histopathologic changes. In conclusion, our data indicate that the pathogenesis of different inherited and acquired muscle disorders involves annexin overexpression, probably because these proteins actively participate in the plasmalemma repair process. The positive correlation between annexin A1 and A2 and clinical severity, as well as muscle histopathology, suggests that their level may be a prognostic indicator of disease.
authors.affiliation: IRCCS E. Medea, Associazione La Nostra Famiglia, Bosisio Parini, Lecco, Italy.
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.forename: Francesca
authors.initials: F
authors.lastname: Magri
authors.forename: Antonio
authors.initials: A
authors.lastname: Toscano
authors.forename: Luciano
authors.initials: L
authors.lastname: Merlini
authors.forename: Francesco
authors.initials: F
authors.lastname: Fortunato
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.forename: Carmelo
authors.initials: C
authors.lastname: Rodolico
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prelle
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
authors.forename: Mohammed
authors.initials: M
authors.lastname: Aguennouz
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ciscato
authors.forename: Antonino
authors.initials: A
authors.lastname: Uncini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017305:Annexin A1 / Q000235:genetics*; D017306:Annexin A2 / Q000235:genetics*; D000073939:Dysferlin; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D008875:Middle Aged; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics*; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype; D011379:Prognosis
chemical_list: D017305:Annexin A1; D017306:Annexin A2; C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins