In other species: birds , fowls , chicken , turkey , Japanese quail

Categories: Nervous system phene

Single-gene trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2025

Cross-species summary: Most vertebrates have left/right independent unilateral motor control. The left brain hemisphere controls the right side of the body and the right brain hemisphere controls the left side of the body. This is achieved by motor neurons in the corticospinal tract crossing to the contralateral side at the level of the brainstem. In the spinal cord, a midline barrier exists that prevents axons from re-crossing. The transmembrane protein ephrin-B3 (EFNB3) is a key molecule required for establishing this spinal midline barrier and correct axon guidance (Kullander et al. 2001; Yokoyama et al. 2001).
Flight in birds evolved through patterning of the wings from forelimbs and transition from alternating gait to synchronous wing flapping. During bird evolution, EFNB3 function and the spinal midline barrier was lost, which resulted in synchronous wing flapping (Haimson et al. 2021).

Species-specific name: Congenital mirror movement disorder 1

Species-specific symbol: CMM1

Mapping: Parametric linkage analysis in a family with 3 affected and 8 unaffected offspring "identified seven intervals on seven different chromosomes, spanning a total of 55 Mb with a maximum logarithm of odds (LOD) score of 2.20. Autozygosity mapping in the three affected siblings identified 72 homozygous regions with shared haplotypes. After combining the results of linkage and autozygosity mapping, five intervals on five different chromosomes spanning 43.2 Mb remained" (Schwarz et al. 2025).

Molecular basis: Schwarz et al. (2025) "used linkage and autozygosity mapping followed by whole-genome sequencing of 3 affected dogs and 1489 control dogs" and identified "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)."

Clinical features: Schwarz et al. (2025): "Three of 11 puppies in a litter of Weimaraner dogs exhibited an abnormal gait characterized by synchronized saltatorial locomotion." ... "The initial presentation included tetraparesis and ataxia on all four limbs with the pelvic limbs being more severely affected. Difficulty in rising on the pelvic limbs and stumbling on the thoracic limbs were observed. The pelvic limb gait showed a bunny-hopping appearance with synchronized saltatorial locomotion. Saltatorial gait was also present on the thoracic limbs. Behavior and mentation were normal and appeared similar between affected and unaffected dogs." The affected puppies from Schwarz et al. 2025 were euthanized at 8 weeks of age and further development of their gait abnormalities was not investigated.
Efnb3^-/- knockout mice exhibit a similar abnormal gait phenotype characterized by bunny-hopping and saltatorial locomotion (Kullander et al. 2001; Yokoyama et a. 2001).

Pathology: Schwarz et al. (2025): "No pathological changes were observed in any of the three affected Weimaraner puppies during a full-body postmortem examination. Systematic histological analyses of the brains, spinal cords, peripheral nerves, muscles, and all other organ systems with any of the stains used failed to identify any abnormal composition, aberrant structures, or any other lesions."
In Efnb3^-/- mice, subtle neuroantomical changes and motor neurons crossing the spinal midline have been demonstrated (Kullander et al. 2001; Yokoyama et a. 2001). 

Breed: Weimaraner (Dog) (VBO_0201401).
Breeds in which the phene or likely causal variants have been documented. If a likely causal variant has been documented, see variant-specific breed information in the variant table. (Breed information may be incomplete).

Associated gene: