Schwarz, Cleo;
Bartenschlager, Florian;
Kershaw, Olivia;
Braun, Judith;
Guevar, Julien;
Jagannathan, Vidhya;
Epplen, Jörg T;
... Leeb, Tosso; + view all
(2025)
EFNB3 Frameshift Variant in Weimaraner Dogs with a Condition Resembling a Congenital Mirror Movement Disorder.
Movement Disorders
10.1002/mds.30243.
(In press).
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Abstract
Background: Congenital mirror movement disorders (CMMs) are clinically and genetically heterogeneous in human patients. CMMs have not been documented to occur spontaneously in animals. // Objective: 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. // Methods: 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. // Results: 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. // Conclusions: 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 International Parkinson and Movement Disorder Society.
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