背景:神经轴索性营养不良(NAD)是一组遗传性神经退行性疾病,其特征主要是在整个中枢神经系统中存在球体(肿胀的轴突)。在人类中,NAD是异构的,临床和遗传。NAD也被描述为在大型动物模型中自然发生。比如狗。一种新发现的小型美国牧羊犬(MAS)疾病,由缓慢进展的神经退行性综合征组成,通过组织病理学诊断为NAD。
目的:描述临床和病理表型,并鉴定潜在的遗传原因。
方法:临床和死后评估,结合全基因组关联研究和自合性作图方法,其次是全基因组测序。
结果:受影响的狗通常是年轻的成年人,表现出异常步态,其特征是骨盆肢体无力和共济失调。潜在的遗传原因被确定为编码环指蛋白170的RNF170中的1-bp(碱基对)缺失,该缺失以常染色体隐性模式完全分离。预计该缺失会产生移码(XM_038559916.1:c.367delG)和RNF170蛋白的早期截短(XP_038415844.1:(p。Ala123Glnfs*11))。这种犬RNF170变体的年龄估计约为30岁,在MAS品种的生殖隔离之前。
结论:RNF170变体先前在患有常染色体隐性痉挛性截瘫-85(SPG85)的人类患者中鉴定;该临床表型显示与本文所述的狗的相似性。因此,我们建议这种新型MASNAD可以作为等效人类疾病的优秀大型动物模型,特别是因为受影响的狗显示出相对较长的寿命,这代表了治疗试验的机会。©2024作者(S)。由WileyPeriodicalsLLC代表国际帕金森症和运动障碍协会出版的运动障碍。
BACKGROUND: Neuroaxonal dystrophy (NAD) is a group of inherited neurodegenerative disorders characterized primarily by the presence of spheroids (swollen axons) throughout the central nervous system. In humans, NAD is heterogeneous, both clinically and genetically. NAD has also been described to naturally occur in large animal models, such as dogs. A newly recognized disorder in Miniature American Shepherd dogs (MAS), consisting of a slowly progressive neurodegenerative syndrome, was diagnosed as NAD via histopathology.
OBJECTIVE: To describe the clinical and pathological phenotype together with the identification of the underlying genetic cause.
METHODS: Clinical and postmortem evaluations, together with a genome-wide association study and autozygosity mapping approach, followed by whole-genome sequencing.
RESULTS: Affected dogs were typically young adults and displayed an abnormal gait characterized by pelvic limb weakness and ataxia. The underlying genetic cause was identified as a 1-bp (base pair) deletion in RNF170 encoding ring finger protein 170, which perfectly segregates in an autosomal recessive pattern. This deletion is predicted to create a frameshift (XM_038559916.1:c.367delG) and early truncation of the RNF170 protein (XP_038415844.1:(p.Ala123Glnfs*11)). The age of this canine RNF170 variant was estimated at ~30 years, before the reproductive isolation of the MAS breed.
CONCLUSIONS: RNF170 variants were previously identified in human patients with autosomal recessive spastic paraplegia-85 (SPG85); this clinical phenotype shows similarities to the dogs described herein. We therefore propose that this novel MAS NAD could serve as an excellent large animal model for equivalent human diseases, particularly since affected dogs demonstrate a relatively long lifespan, which represents an opportunity for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.