1. Congenital mirror movements are associated with defective polymerization of RAD51
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Trouillard, Oriane, Dupaigne, Pauline, Dunoyer, Margaux, Doulazmi, Mohamed, Herlin, Morten Krogh, Frismand, Solène, Riou, Audrey, Legros, Véronique, Chevreux, Guillaume, Veaute, Xavier, Busso, Didier, Fouquet, Coralie, Saint-Martin, Cécile, Méneret, Aurélie, Trembleau, Alain, Dusart, Isabelle, Dubacq, Caroline, Roze, Emmanuel, Développement et plasticité des réseaux neuronaux = Development and Plasticity of Neural Networks (NPS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Mouvement, Investigations, Thérapeutique. Mouvement normal et anormal : physiopathologie et thérapeutique expérimentale [ICM Paris] (Mov’It), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Maintenance des génomes, Microscopies Moléculaire et Bionanosciences, Centre National de la Recherche Scientifique-Université Paris Sud, Maintenance des génomes, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Departement of clinical genetics, Aarhus University Hospital, Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de neurologie [Rennes], Université de Rennes (UR), Université de Paris, CNRS, Institut Jacques Monod, Paris, France, Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Développement, évolution et plasticité du système nerveux (DEPSN), Centre National de la Recherche Scientifique (CNRS), 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 (ANR- 10-LABX-65) supported by French state funds managed by the ANR within the Investissements d’Avenir program (ANR-11-IDEX-0004-02)., ANR-18-CE16-0005,Momic,La décussation du faisceau corticospinal et la latéralisation du contrôle moteur : le paradigme des Mouvements Miroirs Congénitaux (MoMiC)(2018), ANR-14-CE13-0004,AxoDevo,Evolution du guidage axonal(2014), and ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011)
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[SDV]Life Sciences [q-bio] - Abstract
International audience; 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 characterized the functions of RAD51 altered by non-truncating variants using biochemical approaches. Results. The level of wild-type RAD51 protein was lower in all the CMM patients' cells compared with their non-carrier relatives. The reduction was less pronounced in asymptomatic carriers. In vitro, mutant RAD51 proteins showed loss-of-function for polymerization, DNA binding, and strand exchange activity. Conclusion. Our study demonstrates that RAD51 haploinsufficiency, including loss-offunction of non-truncating variants, results in CMM. The incomplete penetrance likely results from post-transcriptional compensation. Changes in RAD51 levels and/or polymerization properties could influence guidance of the corticospinal axons during development. Our findings open up new perspectives to understand the role of RAD51 in neurodevelopment.
- Published
- 2023