Making sense of missense variants in TTN-related congenital myopathies.
Making sense of missense variants in TTN-related congenital myopathies.
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TTN相关先天性肌病的错义变异的意义
DOI：
10.1007/s00401-020-02257-0
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发表时间：
2021-03
影响因子：
12.7
通讯作者：
Gautel M
中科院分区：
文献类型：
--
作者：
Rees M;Nikoopour R;Fukuzawa A;Kho AL;Fernandez-Garcia MA;Wraige E;Bodi I;Deshpande C;Özdemir Ö;Daimagüler HS;Pfuhl M;Holt M;Brandmeier B;Grover S;Fluss J;Longman C;Farrugia ME;Matthews E;Hanna M;Muntoni F;Sarkozy A;Phadke R;Quinlivan R;Oates EC;Schröder R;Thiel C;Reimann J;Voermans N;Erasmus C;Kamsteeg EJ;Konersman C;Grosmann C;McKee S;Tirupathi S;Moore SA;Wilichowski E;Hobbiebrunken E;Dekomien G;Richard I;Van den Bergh P;Domínguez-González C;Cirak S;Ferreiro A;Jungbluth H;Gautel M
由TTN编码的肌节蛋白肌联蛋白的突变正在成为肌病的常见原因。然而，TTN相关肌病的诊断通常并不简单，这是由于与其他肌病的临床病理重叠以及对照人群中TTN变体的流行。在这里，我们提出了一个结合临床病理学，遗传学和生物物理学的方法来诊断TTN相关的肌病和TTN错义变体的致病性确定。我们确定了30例原发性TTN相关先天性肌病（CM）和两个截短变异，或一个截短和一个错义TTN变异，或一个TTN错义变异纯合子。我们发现TTN相关肌病与其他肌病有相当大的重叠，但强烈建议结合某些临床病理特征。通常在出生时出现，临床病程的特征是虚弱、痉挛、脊柱侧弯和呼吸道症状的不同进展，但眼外肌保留。心脏受累取决于不同的位置。我们的生物物理学分析表明，与CM相关的错义突变是强烈的不稳定性，并发挥其作用时，截断背景或纯合性表达。我们假设，不稳定TTN错义突变表型截短变异，是隐性肌钙蛋白病的一个关键致病特征，可能适合治疗干预。在线版本包含补充材料，可通过10.1007/s 00401 -020-02257-0获得。
Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention. The online version contains supplementary material available at 10.1007/s00401-020-02257-0.
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影响因子：
16.6
作者：
Giganti D;Yan K;Badilla CL;Fernandez JM;Alegre-Cebollada J
通讯作者：
Alegre-Cebollada J
影响因子：
9.8
作者：
Hackman, P;Vihola, A;Udd, B
通讯作者：
Udd, B
影响因子：
5.4
作者：
Begay RL;Graw S;Sinagra G;Merlo M;Slavov D;Gowan K;Jones KL;Barbati G;Spezzacatene A;Brun F;Di Lenarda A;Smith JE;Granzier HL;Mestroni L;Taylor M;Familial Cardiomyopathy Registry
通讯作者：
Familial Cardiomyopathy Registry
影响因子：
4
作者：
Fukuzawa, Atsushi;Lange, Stephan;Gautel, Mathias
通讯作者：
Gautel, Mathias
影响因子：
2.7
作者：
DANGOOR, M;SILBERSTEIN, L;MUHLRAD, A
通讯作者：
MUHLRAD, A