Harris Elizabeth, Töpf Ana, Vihola Anna, Evilä Anni, Barresi Rita, Hudson Judith, Hackman Peter, Herron Brian, MacArthur Daniel, Lochmüller Hanns, Bushby Kate, Udd Bjarne, Straub Volker
Newcastle University, John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle upon Tyne, UK.
Folkhälsan Institute of Genetics, Helsinki University, Helsinki, Finland.
Neuromuscul Disord. 2017 Nov;27(11):1009-1017. doi: 10.1016/j.nmd.2017.06.013. Epub 2017 Jun 22.
Mutations in the gene encoding the giant skeletal muscle protein titin are associated with a variety of muscle disorders, including recessive congenital myopathies ±cardiomyopathy, limb girdle muscular dystrophy (LGMD) and late onset dominant distal myopathy. Heterozygous truncating mutations have also been linked to dilated cardiomyopathy. The phenotypic spectrum of titinopathies is emerging and expanding, as next generation sequencing techniques make this large gene amenable to sequencing. We undertook whole exome sequencing in four individuals with LGMD. An essential splice site mutation, previously reported in dilated cardiomyopathy, was identified in all families in combination with a second truncating mutation. Affected individuals presented with childhood onset proximal weakness associated with joint contractures and elevated CK. Cardiac dysfunction was present in two individuals. Muscle biopsy showed increased internal nuclei and immunoblotting identified reduction or absence of calpain-3 and demonstrated a marked reduction of C-terminal titin fragments. We confirm the co-occurrence of cardiac and skeletal myopathies associated with recessive truncating titin mutations. Compound heterozygosity of a truncating mutation previously associated with dilated cardiomyopathy and a 'second truncation' in TTN was identified as causative in our skeletal myopathy patients. These findings add to the complexity of interpretation and genetic counselling for titin mutations.
编码巨大骨骼肌蛋白肌联蛋白的基因突变与多种肌肉疾病相关，包括隐性先天性肌病±心肌病、肢带型肌营养不良（LGMD）和晚发型显性远端肌病。杂合性截短突变也与扩张型心肌病有关。随着新一代测序技术使这个大基因适合测序，肌联蛋白病的表型谱正在出现并不断扩大。我们对4例LGMD患者进行了全外显子组测序。在所有家系中均发现了一个先前在扩张型心肌病中报道的关键剪接位点突变，并伴有第二个截短突变。受影响个体表现为儿童期起病的近端肌无力，伴有关节挛缩和肌酸激酶升高。两名个体存在心脏功能障碍。肌肉活检显示内部细胞核增多，免疫印迹法检测发现钙蛋白酶-3减少或缺失，并显示肌联蛋白C末端片段显著减少。我们证实了与隐性截短型肌联蛋白突变相关的心脏和骨骼肌疾病同时存在。在我们的骨骼肌病患者中，先前与扩张型心肌病相关的截短突变和TTN中的“第二个截短”的复合杂合性被确定为病因。这些发现增加了肌联蛋白突变解释和遗传咨询的复杂性。
