Recessive mutations in proximal I-band of TTN gene cause severe congenital multi-minicore disease without cardiac involvement
Recessive mutations in proximal I-band of TTN gene cause severe congenital multi-minicore disease without cardiac involvement
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TTN基因近端I带的隐性突变导致严重的先天性多微小核病，但不累及心脏
DOI：
10.1016/j.nmd.2019.03.007
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发表时间：
2019-05-01
影响因子：
2.8
通讯作者：
Xiong, Hui
中科院分区：
文献类型：
--
作者：
Ge, Lin;Fu, Xiaona;Xiong, Hui
肌联蛋白由TTN基因编码，是肌节的主要成分之一。它不仅参与维持心肌和骨骼肌的结构，还参与它们的发育、可伸展性、弹性和信号事件。先天性肌钙蛋白病日益成为轴性优势型先天性肌病的一种重要而常见的形式。TTN在先天性肌钙蛋白病和小儿心脏病中的病理生理作用还有待探讨。在这里，我们描述了两个女性同胞的表型谁开发了严重的先天性多微核疾病，心脏不受影响。通过全外显子组测序进行的遗传学研究证实了复合杂合TTN突变（c.15496+1G>A，p.5166_5258de1; c.18597_18598insC，p.Thr6200Hisfs*15），对应于近端I带的IG结构域。通过体外小基因分析证实了导致外显子跳跃的异常剪接。我们的研究结果表明，TTN突变影响近端I带的IG结构域可能是骨骼肌严重先天性缺陷的原因，而没有严重的心脏受累，从而提供证据的假设，先天性肌联蛋白病患者携带双等位基因N2 BA唯一的突变是在较低的心脏风险比那些与其他组合的突变。同时，本研究也从实验上证实了TTN隐性截短突变体的假说，从而支持了先前报道的基因型-表型相关性。(C)2019由Elsevier B. V.出版
Titin, encoded by the gene TTN, is one of the main sarcomere components. It is involved in not only maintaining the structure of cardiac and skeletal muscles, but also in their development, extensibility, elasticity, and signaling events. Congenital titinopathy increasingly appears an important and common form of axial predominant congenital myopathy. The pathophysiological role of TTN in congenital titinopathy and pediatric heart diseases is yet to be explored. Here, we delineate the phenotype of two female siblings who developed severe congenital multi-minicore disease without cardiac involvement. Genetic investigation by whole exome sequencing demonstrated compound heterozygous TTN mutations (c.15496+1G>A, p.5166_5258de1; c.18597_18598insC, p.Thr6200Hisfs*15), corresponding to the Ig domain of the proximal I-band. Aberrant splicing causing exon skipping was verified by in vitro minigene analysis. Our results suggest that TTN mutations affecting the Ig domain of the proximal I-band may be a cause of severe congenital defect in skeletal muscles without severe cardiac involvement, thereby providing evidence for the hypothesis that congenital titinopathy patients carrying biallelic N2BA only mutations are at lower cardiac risk than those with other combinations of mutations. Meanwhile, this study confirm the hypothesis on recessive truncating variants of TTN experimentally and thus support earlier reported genotype-phenotype correlations. (C) 2019 Published by Elsevier B.V.