Cagliani Rachele, Magri Francesca, Toscano Antonio, Merlini Luciano, Fortunato Francesco, Lamperti Costanza, Rodolico Carmelo, Prelle Alessandro, Sironi Manuela, Aguennouz Mohammed, Ciscato Patrizia, Uncini Antonino, Moggio Maurizio, Bresolin Nereo, Comi Giacomo P
IRCCS E. Medea, Associazione La Nostra Famiglia, Bosisio Parini, Lecco, Italy.
Hum Mutat. 2005 Sep;26(3):283. doi: 10.1002/humu.9364.
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.
DYSF基因突变是两种主要肌肉疾病的基础：肢带型肌营养不良症（LGMD）2B和宫下肌病（MM）。肌膜蛋白参与肌肉膜修复，被认为在肌膜处与其他肌膜蛋白分子以及膜联蛋白A1和A2相互作用。我们在一大群肌膜蛋白病患者中进行了基因型/表型相关性研究，并探讨了膜联蛋白作为LGMD - 2B和MM修饰因子的可能作用。特别是，对27名肌膜蛋白病受试者进行了临床检查、肌膜蛋白表达和基因分析。在LGMD - 2B/MM受试者以及患有其他肌肉疾病的患者中研究了A1和A2膜联蛋白的表达。我们鉴定出24种不同的DYSF突变，其中10种是新发现的。我们未观察到突变类型与临床表型之间存在明显相关性，但发现MM患者在生命早期出现肌肉症状的时间明显早于LGMD患者。值得注意的是，与对照组相比，肌膜蛋白病患者和患有其他肌肉疾病的受试者两种膜联蛋白的表达水平更高；膜联蛋白表达水平与临床严重程度评分之间存在显著相关性。此外，膜联蛋白含量与肌肉组织病理学变化程度平行。总之，我们的数据表明，不同遗传性和获得性肌肉疾病的发病机制涉及膜联蛋白过表达，可能是因为这些蛋白质积极参与质膜修复过程。膜联蛋白A1和A2与临床严重程度以及肌肉组织病理学之间的正相关表明，它们的水平可能是疾病的预后指标。
