Letko Anna, Brülisauer Franz, Häfliger Irene M, Corr Eilidh, Scholes Sandra, Drögemüller Cord
Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern 3012, Switzerland.
SRUC Veterinary Services, Pentlands Science Park, Bush Estate Loan, Penicuik, Midlothian EH26 0PZ, United Kingdom.
Genomics. 2023 Sep;115(5):110689. doi: 10.1016/j.ygeno.2023.110689. Epub 2023 Jul 23.
In North Country Cheviot lambs with early-onset progressive ataxia and motor neuron degeneration, whole-genome sequencing identified a homozygous loss-of-function variant in the ovine transmembrane and coiled-coil domains (TMCO6) gene. The familial recessive form of motor neuron disease in sheep is due to a pathogenic 4 bp deletion leading to a 50% protein truncation that is assumed to result in the absence of a functional TMCO6. This uncharacterised protein is proposed to interact with ubiquilin 1 which is associated with Alzheimer's disease, whereas sporadic forms of amyotrophic lateral sclerosis are caused by variants in UBQLN2. Our findings provide a first spontaneous animal model for TMCO6, which could have implications in the studies of other comparative neurodegenerative diseases. In addition, these results will allow the design of a genetic test to prevent the occurrence of this fatal disease in the affected sheep population.
在患有早发性进行性共济失调和运动神经元变性的北国切维厄特羊中，全基因组测序在绵羊跨膜和卷曲螺旋结构域（TMCO6）基因中鉴定出一个纯合功能丧失变异。绵羊运动神经元疾病的家族性隐性形式是由于一个致病性的4bp缺失，导致蛋白质截短50%，推测这会导致功能性TMCO6缺失。这种未被表征的蛋白质被认为与泛素连接蛋白1相互作用，而泛素连接蛋白1与阿尔茨海默病相关，而散发性肌萎缩侧索硬化症是由UBQLN2中的变异引起的。我们的研究结果为TMCO6提供了首个自发动物模型，这可能对其他比较神经退行性疾病的研究有启示。此外，这些结果将有助于设计一种基因检测方法，以预防受影响绵羊群体中这种致命疾病的发生。
