Schwarz Cleo, Bartenschlager Florian, Kershaw Olivia, Braun Judith, Guevar Julien, Jagannathan Vidhya, Epplen Jörg T, Reineking Wencke, Baumgärtner Wolfgang, Bhatia Kailash P, Gruber Achim D, Leeb Tosso
Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
Mov Disord. 2025 Sep;40(9):1883-1891. doi: 10.1002/mds.30243. Epub 2025 May 22.
Congenital mirror movement disorders (CMMs) are clinically and genetically heterogeneous in human patients. CMMs have not been documented to occur spontaneously in animals.
The objective of this work was to document the first case of CMMs spontaneously occurring in Weimaraner dogs and to identify the underlying genetic cause.
Clinical and pathological investigations were performed. Genetic investigations used linkage and autozygosity mapping followed by whole-genome sequencing of 3 affected dogs and 1489 control dogs to identify disease-associated variants.
Three of 11 puppies in a litter of Weimaraner dogs exhibited an abnormal gait characterized by synchronized saltatorial locomotion. Their phenotype was tentatively termed congenital mirror movement disorder 1 (CMM1). The underlying genetic cause was identified as a 2-bp duplication in EFNB3 encoding ephrin-B3, a transmembrane protein important for axon guidance and spinal midline barrier formation during neurodevelopment. The identified variant, XM_038536724.1:c.643_644dup, is predicted to lead to a frameshift and introduction of a premature stop codon XP_038392652.1:p.(Ala216Valfs*79). CMM1 is inherited as an autosomal recessive trait in these dogs.
Similar to humans, CMMs may occur in dogs as an inherited disease as a result of a spontaneously arisen genetic variant. The CMM1 phenotype in dogs resembles the phenotype of experimentally induced Efnb3 knockout mice. So far, no human patients with EFNB3-related CMMs have been reported. Our study provides the first naturally occurring large-animal model for CMMs. EFNB3 should be considered a candidate gene in human CMM patients with unclear disease etiology. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
先天性镜像运动障碍（CMMs）在人类患者中在临床和遗传方面具有异质性。尚未有文献记载CMMs在动物中自发发生。
本研究的目的是记录威玛猎犬中首例自发发生的CMMs病例，并确定潜在的遗传原因。
进行了临床和病理调查。遗传调查采用连锁分析和纯合性定位，随后对3只患病犬和1489只对照犬进行全基因组测序，以确定与疾病相关的变异。
一窝威玛猎犬的11只幼犬中有3只表现出异常步态，其特征为同步跳跃运动。它们的表型暂定为先天性镜像运动障碍1型（CMM1）。潜在的遗传原因被确定为EFNB3基因中的一个2碱基对重复，该基因编码ephrin-B3，这是一种在神经发育过程中对轴突导向和脊髓中线屏障形成很重要的跨膜蛋白。所鉴定的变异体XM_038536724.1:c.643_644dup预计会导致移码，并引入一个提前终止密码子XP_038392652.1:p.(Ala216Valfs*79)。CMM1在这些犬中以常染色体隐性性状遗传。
与人类相似，CMMs可能作为一种由自发产生的遗传变异导致的遗传性疾病出现在犬类中。犬类中的CMM1表型类似于实验诱导的Efnb3基因敲除小鼠的表型。到目前为止，尚未有与EFNB3相关的CMMs人类患者的报道。我们的研究为CMMs提供了首个自然发生的大型动物模型。对于疾病病因不明的人类CMM患者，EFNB3应被视为一个候选基因。© 2025作者。由Wiley Periodicals LLC代表国际帕金森和运动障碍协会出版的《运动障碍》。
