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Neurogenetics
Original research
Congenital mirror movements are associated with defective polymerisation of RAD51
  1. Oriane Trouillard1,2,
  2. Pauline Dupaigne3,
  3. Margaux Dunoyer4,
  4. Mohamed Doulazmi5,
  5. Morten Krogh Herlin6,
  6. Solène Frismand7,
  7. Audrey Riou8,
  8. Véronique Legros9,
  9. Guillaume Chevreux9,
  10. Xavier Veaute10,
  11. Didier Busso10,
  12. Coralie Fouquet1,
  13. Cécile Saint-Martin11,
  14. Aurélie Méneret2,12,
  15. Alain Trembleau1,
  16. Isabelle Dusart1,
  17. Caroline Dubacq1,
  18. Emmanuel Roze2,12
  1. 1 INSERM, CNRS, Institut de Biologie Paris Seine, IBPS, Neuroscience Paris Seine, NPS, Sorbonne Université, F-75005 Paris, France
  2. 2 Institut du Cerveau—Paris Brain Institute—ICM, Inserm, CNRS, AP-HP, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France
  3. 3 Genome Maintenance and Molecular Microscopy UMR9019 CNRS, Université Paris-Saclay, Gustave Roussy, F-94805 Villejuif Cedex, France
  4. 4 Hôpital Pitié-Salpêtrière, Département de Neurologie, AP-HP, Paris, France
  5. 5 INSERM, CNRS, Institut de Biologie Paris Seine, IBPS, Biological Adaptation and Ageing, B2A, Sorbonne Université, F-75005 Paris, France
  6. 6 Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
  7. 7 Service de Neurologie, CHRU de Nancy, Nancy, France
  8. 8 Service de génétique clinique & Service de neurologie, CHU Rennes, Rennes, France
  9. 9 CNRS, Institut Jacques Monod, Université Paris Cité, F-75013 Paris, France
  10. 10 Université Paris-Saclay, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, CIGEx/iRCM/IBFJ, Université Paris Cité, F-92260 Fontenay-aux-Roses, France
  11. 11 AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique Médicale, Sorbonne Université, Paris, France
  12. 12 Hôpital Pitié-Salpêtrière, DMU Neuroscience 6, AP-HP, Paris, France
  1. Correspondence to Dr Caroline Dubacq, INSERM, CNRS, Institut de Biologie Paris Seine, IBPS, Neuroscience Paris Seine, NPS, Sorbonne Université, F-75005 Paris, France; caroline.dubacq{at}sorbonne-universite.fr

Abstract

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.

http://dx.doi.org/10.1136/jmg-2023-109189

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • 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.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.