Molecular genetic analysis and establishment of the genetic diagnosis of autosomal recessive malignant limb-girdle muscular dystrophy.

常染色体隐性恶性肢带型肌营养不良症是由Miyoshi等于1966年建立的临床实体。患者从儿童时期开始就表现出肩部、骨盆带和近端肢体肌肉的萎缩。最近，这种疾病的致病基因，肌聚糖（α，β，γ）和巯基蛋白酶;钙蛋白酶3被确定。我们报告了来自三个日本家族的7例常染色体隐性肢带型肌营养不良症2A型（LGMD 2A）患者的临床、病理和遗传分析。平均发病年龄为9.7*3.1岁（平均值 *SD），救护车丢失发生在38.5*2.1岁。肌肉萎缩主要发生在骨盆、肩胛带和近端肢体肌肉。肌肉病理学显示肌原纤维Z、I和A带的斑片状破坏的营养不良性变化。在两个家族中，在calpain 3基因的第1080位确定了相同的G到C突变。该突变导致钙蛋白酶3的蛋白水解位点中的W360 R取代。在第三个家族中还发现了一个移码突变（1796 insA），导致Ca^2+结合结构域缺失。这些结果表明LGMD 2A是由钙蛋白酶3蛋白的缺乏引起的，导致蛋白酶对肌原纤维或肌纤维的蛋白水解活性的激活。我们还与鹿儿岛大学第三内科合作，调查了伴有α-肌聚糖或γ-肌聚糖缺乏症的严重儿童常染色体隐性肌营养不良症患者。

Autosomal recessive malignant limb-girdle muscular dystrophy is a clinical entity established by Dr. Miyoshi et al. in 1966. The patients show the muscular atrophy in the shoulder, pelvic girdles, and proximal limb muscles from childhood. Recently, disease causing genes of this disease, sarcoglycans (alpha, beta, gamma) and thiol proteinase ; calpain 3 were identified. We report on the clinical, pathological, and genetic analyses of seven patients (six men, one women) with autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A) from three Japanese families. The mean age of onset was 9.7*3.1 years (mean*SD), and loss of ambulance occurred at 38.5*2.1 years. Muscular atrophy was predominant in the pelvic, shoulder girdles, and proximal limb muscles. Muscle pathology revealed dystrophic changes with patchy destruction of the myofibrillar Z, I, and A bands. In two families, an identical G to C mutation at position 1080th in the calpain 3 gene was identified. This mutation results in a W360R substitution in the proteolytic site of calpain 3. A frameshift mutation (1796 insA) which results in a deletion of the Ca^<2+> binding domain was also found in the third family. These results suggest that LGMD2A is caused by a deficiency of the calpain 3 protein results in the activation of proteolytic activities of proteases to the myofibrils or muscle fibers. In collaboration with Third Department of Internal Medicine, Kagoshima University, we also investigated the patients with severe childhood autosomal recessive muscular dystrophy with alpha-sarcoglycan or gamma -sarcoglycan deficiency.