Comi G P, Prelle A, Bresolin N, Moggio M, Bardoni A, Gallanti A, Vita G, Toscano A, Ferro M T, Bordoni A
Institute of Clinical Neurology, Dino Ferrari Centre, University of Milano, Italy.
Brain. 1994 Feb;117 ( Pt 1):1-14. doi: 10.1093/brain/117.1.1-a.
We have investigated 59 Becker muscular dystrophy patients, representing 56 independent mutations, to test the hypothesis of predictability of muscle dystrophin expression and clinical phenotype based on location of dystrophin gene mutations. Partial intragenic deletions and duplications account for 82% of the independent mutations, of which 76.7% were deletions and 5.3% duplications. Mutations in which boundaries could be defined, were of in-frame type (35 out of 37, 94.6%, with two exceptions. Eighty-two percent of mutations were located at the distal part of the rod domain (exons 45-60), 9% at domain I (promoter through exon 9) and 9% at proximal and central parts of domain II. Domain I deleted patients tended to have a worse clinical phenotype, with earlier presentation, faster progression rate and lower dystrophin expression, while distal rod domain deleted patients showed a more classic Becker muscular dystrophy phenotype. Between these two groups, only the differences in the immunohistochemical patterns of dystrophin expression and disease progression rate were statistically significant. Partial clinical and biochemical heterogeneity was observed in the distal domain II patient group, due to the presence of few patients covering the extremities of clinical severity. Two asymptomatic patients had deletions located in the central (exons 41-44) and distal parts (exons 50-53) of the rod domain. Severe myalgia and cramps were often reported as early onset symptoms (18 out of 59): no correlation was found between this symptomatology and the location of the mutation. Relative levels of muscle dystrophin correlated with immunohistochemical patterns of subsarcolemma staining. Dystrophin levels (as estimated by 30 kDa antibody immuno-reactivity) correlated with age of reaching a moderate degree of muscle involvement as well as with delay in reaching that stage, a parameter of disease progression rate. Our data confirm that different Becker muscular dystrophy gene in-frame mutations have different effects on dystrophin expression and clinical severity, indicating several functional roles of the dystrophin domains.
我们研究了59例贝克型肌营养不良患者，这些患者代表56种独立突变，以检验基于肌营养不良蛋白基因突变位置预测肌肉中肌营养不良蛋白表达及临床表型这一假设。部分基因内缺失和重复占独立突变的82%，其中76.7%为缺失，5.3%为重复。边界能够确定的突变属于读码框内类型（37例中有35例，占94.6%，有两个例外）。82%的突变位于杆状结构域远端部分（外显子45 - 60），9%位于结构域I（从启动子到外显子9），9%位于结构域II的近端和中部。结构域I缺失的患者临床表型往往更差，起病更早，进展速度更快，肌营养不良蛋白表达更低，而杆状结构域远端缺失的患者表现出更典型的贝克型肌营养不良表型。在这两组之间，只有肌营养不良蛋白表达的免疫组化模式和疾病进展速度的差异具有统计学意义。由于覆盖临床严重程度两端的患者较少，在结构域II远端患者组中观察到部分临床和生化异质性。两名无症状患者的缺失位于杆状结构域中部（外显子41 - 44）和远端部分（外显子50 - 53）。严重肌痛和痉挛常被报告为早期症状（59例中有18例）：未发现这种症状与突变位置之间存在相关性。肌肉中肌营养不良蛋白的相对水平与肌膜下染色的免疫组化模式相关。肌营养不良蛋白水平（通过30 kDa抗体免疫反应性估计）与达到中度肌肉受累程度的年龄以及达到该阶段的延迟相关，后者是疾病进展速度的一个参数。我们的数据证实，不同的贝克型肌营养不良基因读码框内突变对肌营养不良蛋白表达和临床严重程度有不同影响，表明肌营养不良蛋白结构域具有多种功能作用。
