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肌营养不良症是由Dr. Miyoshi等人于1966年建立的一种临床实体。患者自幼出现肩部、骨盆带及肢体近端肌肉萎缩。最近，该病的致病基因，肌聚糖（α, β, γ）和巯基蛋白酶；确定了calpain3。我们报告了来自三个日本家庭的7例（6男1女）常染色体隐性肢体带状肌营养不良症2A型（LGMD2A）的临床、病理和遗传分析。平均发病年龄为9.7*3.1岁（mean*SD），失救护车年龄为38.5*2.1岁。肌肉萎缩主要发生在骨盆、肩带和肢体近端肌肉。肌肉病理显示肌纤维Z、I、A带呈斑片状破坏。在两个家庭中，在钙蛋白酶3基因的第1080位发现了相同的G到C突变。这种突变导致钙蛋白酶3蛋白水解位点的W360R取代。在第三个家族中也发现了一个移码突变（1796 insA），导致Ca^<2+>结合域的缺失。这些结果表明LGMD2A是由钙蛋白酶3蛋白的缺乏导致肌原纤维或肌肉纤维蛋白酶的蛋白水解活性激活引起的。与鹿儿岛大学内科第三科合作，我们也调查了严重的儿童常染色体隐性肌营养不良伴α -肌聚糖或γ -肌聚糖缺乏的患者。

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.