在CCDC78中的遗传变异对LMNA相关骨肌肉疾病的影响
Nathaniel P Mohar1,2, Efrem M Cox3,4, Emily Adelizzi1,5
1Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA.
International journal of molecular sciences
|May 11, 2024
概括
在CCDC78基因的一个常见变体加剧了由LMNA突变引起的肢体腰带肌肉缩1B型 (LGMD1B). 这种遗传相互作用导致更严重的肌肉病理,包括肌肉核心,解释疾病的变异性.
科学领域:
- 遗传学 遗传学 是一个
- 分子生物学分子生物学
- 神经肌肉疾病 神经肌肉疾病
背景情况:
- 肢体腰带肌肉缩1B型 (LGMD1B) 是由LMNA基因突变引起的,但疾病的严重程度有很大差异.
- 怀疑这种变异性是由于遗传背景差异造成的,这些差异尚未得到很好的描述.
- 特定的肌肉纤维异常,如核心,通常与LGMD1B无关.
研究的目的:
- 在一个多代家族中识别导致LGMD1B变异性表型的遗传变异.
- 调查所观察到的肌肉病理背后的分子机制,包括肌肉核心的存在.
主要方法:
- 全基因组测序 (WGS) 用于识别家族中与严重的LGMD1B表型分离的DNA变异.
- 分析骨肌肉活检以检查肌肉纤维结构,包括核的存在和蛋白质定位.
- 在家族血统中对已识别的变异进行分离分析.
主要成果:
- 导致拼接部位缺陷的主导LMNA突变被确定为家族LGMD1B的主要原因.
- 全基因组测序确定了21种与更严重疾病分离的变异,包括CCDC78.8中常见的变异.
- 患有LMNA突变和CCDC78变异的家族成员表现出肌肉核心积累了CCDC78和RyR1,而只有LMNA突变的较少受影响的成员没有这些肌肉核心.
结论:
- 一种常见的CCDC78变种作为修饰剂,显著增加由LMNA突变引起的LGMD1B的严重程度.
- 综合遗传效应导致不同的肌肉病理,包括形成含有CCDC78和RyR1.1的肌肉核心.
- 这项研究阐明了解释LGMD1B表型变异的遗传相互作用,并突出了CCDC78作为潜在的治疗点.
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