Background Mirror movements are involuntary movements of one hand that mirror intentional movements of the other hand. Congenital mirror movements (CMM) is a rare genetic disorder with autosomal dominant inheritance, in which mirror movements are the main neurological manifestation. CMM is associated with an abnormal decussation of the corticospinal tract, a major motor tract for voluntary movements. RAD51 is known to play a key role in homologous recombination with a critical function in DNA repair. While RAD51 haploinsufficiency was first proposed to explain CMM, other mechanisms could be involved.
Methods We performed Sanger sequencing of RAD51 in five newly identified CMM families to identify new pathogenic variants. We further investigated the expression of wild-type and mutant RAD51 in the patients’ lymphoblasts at mRNA and protein levels. We then characterised the functions of RAD51 altered by non-truncating variants using biochemical approaches.
Results The level of wild-type RAD51 protein was lower in the cells of all patients with CMM compared with their non-carrier relatives. The reduction was less pronounced in asymptomatic carriers. In vitro, mutant RAD51 proteins showed loss-of-function for polymerisation, DNA binding and strand exchange activity.
Conclusion Our study demonstrates that RAD51 haploinsufficiency, including loss-of-function of non-truncating variants, results in CMM. The incomplete penetrance likely results from post-transcriptional compensation. Changes in RAD51 levels and/or polymerisation properties could influence guidance of the corticospinal axons during development. Our findings open up new perspectives to understand the role of RAD51 in neurodevelopment.
- gene expression
- germ-line mutation
- human genetics
- movement disorders
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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CD and ER are joint senior authors.
Contributors ID, CD and ER designed the work. OT, PD, MDu, MKH, SF, AR, VL, GC, XV, DB, CF, CS-M and AM acquired data. OT, PD, MDu, MDo analysed data. OT, PD, MDu, MDo and AT interpreted data. OT, CD and ER drafted the work. MDu, MDo, MKH, SF, AR, VL, GC, XV, DB, CF, CS-M, AM, AT and ID revised it for intellectual content. CD and ER contributed equally to this paper. All coauthors have approved the final version of the manuscript. Part of this work was carried out on the DNA & cells bank of the Paris Brain Institute and on the real-time PCR facility of IBPS. CD is responsible for the overall content as guarantor.
Funding This work was supported by the Fondation Desmarest, Merz-Pharma, Elivie, Orkyn, Djillali Mehri, CNRS, INSERM and Sorbonne Université. This work was also funded by grants from the Agence Nationale de la Recherche (ANR) (ANR-14-CE13-0004-01, ANR-18-CE16-0005-02), from the National Institute of Health NIDCD (R01-DC-017989, USA) and it was performed within the framework of LABEX LIFESENSES (ANR10-LABX-65) supported by French state funds managed by the ANR within the Investissements d’Avenir programme (ANR-11-IDEX-0004-02).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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