Black Holly A, Leighton Danielle J, Cleary Elaine M, Rose Elaine, Stephenson Laura, Colville Shuna, Ross David, Warner Jon, Porteous Mary, Gorrie George H, Swingler Robert, Goldstein David, Harms Matthew B, Connick Peter, Pal Suvankar, Aitman Timothy J, Chandran Siddharthan
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
The Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
Neurobiol Aging. 2017 Mar;51:178.e11-178.e20. doi: 10.1016/j.neurobiolaging.2016.12.013. Epub 2016 Dec 21.
Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant. Loss-of-function variants were found in TBK1 in 3 cases and no controls and, separately, in NEK1 in 3 cases and no controls. This study provides an accurate description of the genetic epidemiology of MND in Scotland and provides support for the contribution of both TBK1 and NEK1 to MND susceptibility in the Scottish population.
在过去10年里，人们对运动神经元病（MND）的遗传学认识有了很大进展，包括最近发现MND与TBK1和NEK1基因变异之间存在关联。我们的目的是确定已知MND相关基因中致病变异的频率，并评估TBK1和NEK1基因变异是否会增加苏格兰人群中MND的发病负担。我们对441例患者和400例对照进行了SOD1、TARDBP、OPTN、TBK1和NEK1基因测序。除了44例已知携带C9orf72六核苷酸重复扩增的病例外，我们还鉴定出31例患者和2例对照携带功能丧失或致病变异。在3例患者中发现了TBK1基因的功能丧失变异，对照中未发现；另外，在3例患者中发现了NEK1基因的功能丧失变异，对照中也未发现。本研究准确描述了苏格兰MND的遗传流行病学情况，并支持TBK1和NEK1基因变异对苏格兰人群MND易感性的影响。
