Konersman Chamindra G, Freyermuth Fernande, Winder Thomas L, Lawlor Michael W, Lagier-Tourenne Clotilde, Patel Shailendra B
Department of Neurosciences, University of California San Diego, San Diego, California.
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
Mol Genet Genomic Med. 2017 Nov;5(6):678-691. doi: 10.1002/mgg3.325. Epub 2017 Aug 21.
Nemaline myopathy (NEM) is one of the three major forms of congenital myopathy and is characterized by diffuse muscle weakness, hypotonia, respiratory insufficiency, and the presence of nemaline rod structures on muscle biopsy. Mutations in troponin T1 (TNNT1) is 1 of 10 genes known to cause NEM. To date, only homozygous nonsense mutations or compound heterozygous truncating or internal deletion mutations in TNNT1 gene have been identified in NEM. This extended family is of historical importance as some members were reported in the 1960s as initial evidence that NEM is a hereditary disorder.
Proband and extended family underwent Sanger sequencing for TNNT1. We performed RT-PCR and immunoblot on muscle to assess TNNT1 RNA expression and protein levels in proband and father.
We report a novel heterozygous missense mutation of TNNT1 c.311A>T (p.E104V) that segregated in an autosomal dominant fashion in a large family residing in the United States. Extensive sequencing of the other known genes for NEM failed to identify any other mutant alleles. Muscle biopsies revealed a characteristic pattern of nemaline rods and severe myofiber hypotrophy that was almost entirely restricted to the type 1 fiber population.
This novel mutation alters a residue that is highly conserved among vertebrates. This report highlights not only a family with autosomal dominant inheritance of NEM, but that this novel mutation likely acts via a dominant negative mechanism.
杆状体肌病（NEM）是先天性肌病的三种主要形式之一，其特征为弥漫性肌肉无力、肌张力减退、呼吸功能不全以及肌肉活检时出现杆状体结构。肌钙蛋白T1（TNNT1）基因突变是已知导致NEM的10个基因之一。迄今为止，在NEM中仅鉴定出TNNT1基因的纯合无义突变或复合杂合截短或内部缺失突变。这个大家庭具有历史意义，因为在20世纪60年代有一些成员被报道，作为NEM是一种遗传性疾病的初步证据。
先证者及其大家庭成员接受了TNNT1的桑格测序。我们对肌肉进行了逆转录聚合酶链反应（RT-PCR）和免疫印迹，以评估先证者和其父亲的TNNT1 RNA表达和蛋白水平。
我们报告了TNNT1基因的一个新的杂合错义突变c.311A>T（p.E104V），该突变在美国的一个大家庭中以常染色体显性方式分离。对其他已知的NEM相关基因进行广泛测序未能鉴定出任何其他突变等位基因。肌肉活检显示出杆状体的特征性模式以及严重的肌纤维萎缩，几乎完全局限于I型纤维群体。
这个新突变改变了一个在脊椎动物中高度保守的残基。本报告不仅突出了一个具有NEM常染色体显性遗传的家庭，而且表明这个新突变可能通过显性负性机制起作用。
