PDF(Pubmed)
Abstract：
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive damage to both upper and lower motor neurons. Genetic factors are known to play a crucial role in ALS, as genetic studies not only advance our comprehension of disease mechanisms but also help unravel the complex phenotypes exhibited by patients. To gain further insights into the genetic landscape of ALS in the Chinese population and explore genotype-phenotype correlations among individuals, we conducted whole-genome sequencing to screen genes in 34 Chinese familial ALS (FALS) probands lacking the most common ALS-associated genes. Within this cohort, we identified a rare heterozygous missense mutation in the N-terminal domain of KIF5A (c.86A>G) in one of the probands. This finding is significant as mutations in the KIF5A gene have been implicated in ALS in European cohorts since 2018, predominantly characterized by C-terminal mutations. Analysis of the clinical phenotype within this familial lineage revealed a delayed onset of symptoms, an extended survival duration, and initial manifestations in both upper limbs. These observations underscore the clinical heterogeneity observed in ALS patients harboring KIF5A mutations. In conclusion, our study contributes to the growing body of evidence linking KIF5A to ALS and enhances our understanding of the intricate genetic landscape of this disease.
摘要：
肌萎缩侧索硬化症（ALS）是一种破坏性的神经退行性疾病，其特征是对上下运动神经元的进行性损害。众所周知，遗传因素在ALS中起着至关重要的作用，因为基因研究不仅提高了我们对疾病机制的理解，而且有助于解开患者表现出的复杂表型。为了进一步了解中国人群中ALS的遗传景观，并探索个体之间的基因型-表型相关性，我们进行了全基因组测序,以筛选缺乏最常见ALS相关基因的34位中国家族性ALS(FALS)先证者的基因.在这个群体中，我们在一个先证者的KIF5A的N端结构域中发现了一个罕见的杂合错义突变(c.86A>G)。这一发现具有重要意义，因为自2018年以来，KIF5A基因的突变与欧洲队列中的ALS有关，主要以C端突变为特征。对该家族谱系内的临床表型的分析揭示了症状的延迟发作，延长的生存时间，和两个上肢的初始表现。这些观察结果强调了在具有KIF5A突变的ALS患者中观察到的临床异质性。总之,我们的研究有助于越来越多的证据将KIF5A与ALS联系起来,并增强了我们对这种疾病复杂遗传格局的理解.
