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
INSERM, CNRS, Institut de Biologie Paris Seine, IBPS, Neuroscience Paris Seine, NPS, Sorbonne Université, F-75005 Paris, France.
Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, AP-HP, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France.
J Med Genet. 2023 Nov;60(11):1116-1126. doi: 10.1136/jmg-2023-109189. Epub 2023 Jun 12.
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 haploinsufficiency was first proposed to explain CMM, other mechanisms could be involved.
We performed Sanger sequencing of 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.
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. , mutant RAD51 proteins showed loss-of-function for polymerisation, DNA binding and strand exchange activity.
Our study demonstrates that 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.
镜像运动是一只手的非自主运动，它与另一只手的自主运动相对应。先天性镜像运动（CMM）是一种罕见的常染色体显性遗传疾病，其中镜像运动是主要的神经学表现。CMM与皮质脊髓束的异常交叉有关，皮质脊髓束是自主运动的主要运动通路。已知RAD51在同源重组中起关键作用，在DNA修复中具有重要功能。虽然最初提出单倍体不足来解释CMM，但可能涉及其他机制。
我们对五个新发现的CMM家族进行了桑格测序，以鉴定新的致病变异。我们进一步在mRNA和蛋白质水平上研究了患者淋巴母细胞中野生型和突变型RAD51的表达。然后，我们使用生化方法对非截短变异改变的RAD51的功能进行了表征。
与非携带者亲属相比，所有CMM患者细胞中的野生型RAD51蛋白水平较低。在无症状携带者中，这种降低不太明显。此外，突变型RAD51蛋白在聚合、DNA结合和链交换活性方面表现出功能丧失。
我们的研究表明，单倍体不足，包括非截短变异的功能丧失，会导致CMM。不完全外显率可能是由转录后补偿引起的。RAD51水平和/或聚合特性的变化可能会影响发育过程中皮质脊髓轴突的导向。我们的发现为理解RAD51在神经发育中的作用开辟了新的视角。
