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BCS1L相关疾病:5'-UTR变异将表型转向轴突神经病变

Rotem Orbach¹, Nunziata Maio², Russell J Butterfield³

¹Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

Annals of clinical and translational neurology

|July 15, 2025

概括

这项研究揭示了BCS1L误解变异和5'-UTR调节变异如何影响线粒体疾病. 5'-UTR变体通过允许残留基因表达来减轻严重程度,扩大了BCS1L疾病的临床谱.

科学领域:

遗传学和分子生物学
线粒体生物学线粒体生物学
神经遗传学神经遗传学

背景情况:

BCS1L基因突变与线粒体疾病有关.
了解基因型-表型相关性对于诊断和管理这些复杂的疾病至关重要.
调控变异在疾病严重性中的作用是一个新兴的研究领域.

研究的目的:

调查BCS1L误解变异 (c.838C>T;p.L280F) 和5个阶段UTR变异 (c.-122G>T) 的致病影响.
阐明这些变异如何影响疾病的发病,临床表现和受影响的兄弟姐妹的严重程度.
扩大对BCS1L相关疾病的理解,以及调节因素在疾病调节中的作用.

主要方法:

深度表型和全基因组测序被用来识别遗传变异.
对已识别的BCS1L变异进行了生物化学表征.
用患者衍生纤维细胞培养物的研究评估了变异性致病性和对治疗剂的反应.

主要成果:

在受影响的兄弟姐妹中,在BCS1L中发现了一种致病性误解变体 (p.L280F) 和一个5级UTR变体 (c.-122G>T).
误解变体破坏了线粒体复合体III组合,而5 étaire-UTR变体允许剩余的野生型BCS1L表达,减轻了疾病的严重程度.
生物化学分析证实了变异性致病性,并显示了适度的体外反应对辅酶Q10模拟物.

结论:

这项研究确定了一种较温和的BCS1L相关疾病表型,涉及中枢和外周神经系统功能障碍.
5阶段-UTR变异通过启用残基因表达来调节疾病严重程度,部分抵消误解变异的影响.
评估编码和调节变异对于准确诊断和了解线粒体疾病的病原性至关重要.

关键词:

在 5′-UTR 中.BCS1LL BCS1L 是一个复杂的III复杂的III复杂的运动神经病变是一种运动神经病变.氧化酸化是一种氧化酸化.

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