Comment on Schwarz et al. “EFNB3 Frameshift Variant in Weimaraner Dogs with a Condition Resembling a Congenital Mirror Movement Disorder”

Abstract

We read with great interest the recent publication reporting the study of Weimaraner dog siblings with a hopping gait,¹ that is, a loss of the left–right alternation of limb movements during locomotion. This phenotype was caused by a homozygous pathogenic variant in EFNB3 encoding ephrin B3. In humans, lack of motor control lateralization results in mirror movements (MM). Therefore, the authors suggested that EFNB3 could be a new candidate gene in patients with congenital mirror movements (CMM). To investigate a potential role of EFNB3, we analyzed exome sequencing data from 59 CMM index cases with no pathogenic variant in the known CMM causative genes. We did not identify any variants in the EFNB3 gene. Thus, this gene does not appear to be involved in CMM.

This finding is not unexpected because a hopping gait is not equivalent to MM.² The hopping gait results from a dysfunction of the central pattern generators within the spinal cord. MMs are rather related to anatomical and functional abnormalities of supra-spinal structures, such as abnormal bilateral corticospinal tract (CST) projections to the spinal cord and/or abnormal interhemispheric interactions.² Several lines of evidence support this hypothesis. In mice, a hopping gait was associated with mutations in Dcc, the gene encoding a netrin-1 receptor³ and Epha4, the gene encoding the ephrin-B3 receptor.⁴ Both genes are involved in the guidance at the midline of the CST and commissural spinal neurons. In knock-out mice for Dcc or Epha4, both the CST and spinal circuitry are affected. It is thus difficult to disentangle the respective contribution of these structures to the hopping gait.^{3, 4} Strikingly, conditional deletion of any of these two genes restricted to the spinal cord is sufficient to produce a hopping gait.^{4, 5} Their respective deletion in the CST does not alter stereotypic locomotion.^{3, 4} In particular, deletion of Epha4 within the neocortex results in aberrant bilateral CST projections to the spinal cord while the spinal circuitry is unaffected. These mutants have a normal stereotypic locomotion.^{4, 6} By contrast, they have abnormal bilateral reaching behavior and a hopping gait specifically during adaptive locomotion that requires supra-spinal control,⁶ a phenotype that reflects human MM. Last, mutations of the Dmrt3 gene, encoding a transcription factor involved in the development of commissural spinal interneurons, are associated with the ability to produce alternated gait in horses.⁷ Dmrt3 mutations are present in horse breeds that are able to produce alternated gait at intermediate speeds, without transition to gallop, in which limb movements are symmetrical. This suggests that left–right alternation during locomotion relies on spinal circuitry and is therefore not equivalent to MM.

Altogether, the hopping-gait observed in EFNB3 mutant dogs likely reflects a disruption of the spinal circuitry. Because ephrin-B3 and Epha4 are involved in CST guidance at the midline, these dogs might also have aberrant bilateral CST projections to the spinal cord, but the phenotypic and anatomical data are insufficient to confirm this hypothesis. Because ephrin-B3 has not been associated with human disorders, compensatory mechanisms might mitigate such defects in human.

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

O.T.: 1B, 1C, 3A.

Q.W.: 1A, 3A.

A.M.: 1C, 3B.

C.D.: 1B, 3B.

E.R.: 1A, 1B, 1C, 3A.

O.T.: none. Q.W.: none. A.M.: received honoraria for speeches from Merz-Pharma and Abbvie, and travel funding from Elivie and Merz-Pharma. C.D. E.R.: received honorarium for speech from Orkyn, Aguettant, Elivie, Merz-Pharma, Janssen, Teva, Everpharma and for participating in advisory boards from Merz-Pharma, Elivie, Teva, and BIAL. He received research support from Merz-Pharma, Orkyn, Elivie, Everpharma, Aguettant, enjoy sharing.