Mutation Finding in Patients With Dysferlin Deficiency and Role of the Dysferlin Interacting Proteins Annexin A1 and A2 in Muscular Dystrophies
Mutation Finding in Patients With Dysferlin Deficiency and Role of the Dysferlin Interacting Proteins Annexin A1 and A2 in Muscular Dystrophies
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DOI：
10.1002/humu.9364
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发表时间：
2005-09-01
期刊：
影响因子：
3.9
通讯作者：
Comi, Giacomo P.
中科院分区：
文献类型：
--
作者：
Cagliani, Rachele;Magri, Francesca;Comi, Giacomo P.
DYSF基因的突变是两种主要肌肉疾病的基础：肢体吉莱德肌营养不良症(LGMD)2B和Miyoshi肌病(MM)。Dyferlin参与肌膜修复，并被认为与其他dyferlin分子以及肌膜上的膜联蛋白A1和A2相互作用。我们在一大群性激素异常患者中进行了基因/表型相关性，并探讨了膜联蛋白作为LGMD-2B和MM的调节因子的可能作用，特别是对27名性激素异常患者进行了临床检查、肌膜蛋白表达和遗传分析。研究了A1和A2膜联蛋白在LGMD-2B/MM患者和其他肌肉疾病患者中的表达。我们鉴定了24个不同的DYSF突变，其中10个是新的。我们没有观察到突变类型与临床表型的明显相关性，但MM患者在生活中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，铁代谢障碍患者和患有其他肌肉疾病的患者表达了更高水平的膜联蛋白；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，膜联蛋白的含量与肌肉组织病理变化的程度平行。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的过度表达，可能是因为这些蛋白积极参与了质膜修复过程。Annexin A1和A2与临床严重程度以及肌肉组织病理学呈正相关，提示它们的水平可能是疾病预后的指标。(C)2005年Wiley-Liss，Inc.
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 Al 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. (C) 2005 Wiley-Liss, Inc.