Peeters Kristien, Bervoets Sven, Chamova Teodora, Litvinenko Ivan, De Vriendt Els, Bichev Stoyan, Kancheva Dahlia, Mitev Vanyo, Kennerson Marina, Timmerman Vincent, De Jonghe Peter, Tournev Ivailo, MacMillan John, Jordanova Albena
Molecular Neurogenomics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Hum Mutat. 2015 Mar;36(3):287-91. doi: 10.1002/humu.22744.
The heavy chain 1 of cytoplasmic dynein (DYNC1H1) is responsible for movement of the motor complex along microtubules and recruitment of dynein components. Mutations in DYNC1H1 are associated with spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (HMSN), cortical malformations, or a combination of these. Combining linkage analysis and whole-exome sequencing, we identified a novel dominant defect in the DYNC1H1 tail domain (c.1792C>T, p.Arg598Cys) causing axonal HMSN. Mutation analysis of the tail region in 355 patients identified a de novo mutation (c.791G>T, p.Arg264Leu) in an isolated SMA patient. Her phenotype was more severe than previously described, characterized by multiple congenital contractures and delayed motor milestones, without brain malformations. The mutations in DYNC1H1 increase the interaction with its adaptor BICD2. This relates to previous studies on BICD2 mutations causing a highly similar phenotype. Our findings broaden the genetic heterogeneity and refine the clinical spectrum of DYNC1H1, and have implications for molecular diagnostics of motor neuron diseases.
胞质动力蛋白重链1（DYNC1H1）负责运动复合体沿微管的移动以及动力蛋白组件的募集。DYNC1H1突变与脊髓性肌萎缩症（SMA）、遗传性运动和感觉神经病（HMSN）、皮质畸形或这些病症的组合有关。通过连锁分析和全外显子组测序，我们在DYNC1H1尾部结构域中鉴定出一种新的显性缺陷（c.1792C>T，p.Arg598Cys），可导致轴索性HMSN。对355例患者的尾部区域进行突变分析，在一名孤立性SMA患者中发现了一个新生突变（c.791G>T，p.Arg264Leu）。她的表型比先前描述的更为严重，其特征为多发性先天性挛缩和运动发育迟缓，无脑部畸形。DYNC1H1中的突变增加了其与衔接蛋白BICD2的相互作用。这与先前关于BICD2突变导致高度相似表型的研究相关。我们的发现拓宽了DYNC1H1的遗传异质性并细化了其临床谱，对运动神经元疾病的分子诊断具有重要意义。
