一个Bethlem肌病家系的临床表型及分子遗传学研究  

Clinical and mutation analyses of a Chinese family with Bethlem myopathy

作　　者：杨海坡[1] 张艳芝[2] 丁娟[1] 焦辉[1] 吕俊兰[3] 熊晖[1] 

机构地区：[1]北京大学第一医院儿科,100034 [2]山西省儿童医院 [3]学附属北京儿童医院神经内科

出　　处：《中华医学杂志》2012年第40期2820-2824,共5页National Medical Journal of China

基　　金：北京市自然科学基金（7112133）

摘　　要：目的分析并确立一个连续3代患病的Bethlem肌病家系的临床表型特点及基因突变情况。方法收集先证者及其家系成员的临床资料并提取家庭成员外周血基因组DNA，PCR扩增COL6A1、A2和A3基因的外显子，以琼脂糖凝胶电泳鉴定PCR产物，PCR产物纯化后DNA直接测序，确定基因突变的类型，并进一步分析基因型及表型的关系。取患者皮肤进行成纤维细胞培养，通过特异性免疫荧光染色比较对照组与患者成纤维细胞外基质中Ⅵ型胶原蛋白的表达。结果家系中9例患者临床上符合Bethlera肌病的诊断，其特点为晚婴期出现运动发育落后，肢体无力，走路不稳，蹲下站起困难，远端关节过度松弛，近端关节挛缩，皮肤改变（卷烟纸样瘢痕），智力正常。查血清肌酸激酶轻度升高，肌电图提示肌源性损害。疾病缓慢进展但不影响寿命。7例患者经基因检测均证实存在COL6A1基因第2外显子C．111-129缺失突变，此为国际没有报道过的新突变。与对照组相比，患者成纤维细胞外基质中Ⅵ型胶原蛋白表达明显减少。结论明确了我国一个Bethlem肌病家系的临床特点，该家系符合常染色体显性遗传的遗传方式，其患者存在COL6A1基因第2外显子C．111．129缺失突变。Objective To explore the clinical features and gene mutation of a Chinese family with Bethlem myopathy in three generations. Methods The clinical data of proband and his family members was collected. Genomic DNA from the patient and his family members was extracted routinely from peripheral blood leukocytes. Polymerase chain reaction and DNA direct sequencing were employed to analyze COL6A1, A2 and A3 genes to determine the mutation. And the relationship between genotype and phenotype was analyzed. Furthermore, the patient＇s skin fibroblast was cultured and immunofluorescent staining was performed with anticollagen VI antibody. And the expression pattern of type VI collagen in extracellular matrix between the control and the patient＇s fibroblast was compared. Results In this family, 9 patients conformed to the clinical diagnosis of Bethlem myopathy. The features included motor development delay after late infantile period, generalized muscle weakness, walking unstability, distal hypedaxity, proximal joint contractures, skin changes （including hypertrophic scars） and normal intellectual development. Serum ereatine kinase （CK） level became mildly elevated and electromyography showed myogenic injury. Disease progressed slowly but the lifespan was not affected. Mutation in exon 2 of COL6A1 gene with c. 111-129 deletion was detected in 7 patients in this family. Immunofluorescent staining of type Ⅵ collagen in cultured skin fibroblast showed reduced expression of collagen Ⅵ in extracellular matrix in the patient compared with the control Conclusions Our study has defined the clinical features of Bethlem myopathy. According to molecular genetic analysis, 7 patients in this family have inframe deletion mutations of COL6A1 and they conform to autosomal dominant inheritance. And genetic counseling and prenatal diagnosis are available. This is the first Chinese report of Bethlem myopathy family.

关 键 词：肌营养不良 突变 Bethlem肌病 VI胶原蛋白病 

分 类 号：R746[医药卫生—神经病学与精神病学]