Maurel Cindy, Madji-Hounoum Blandine, Thepault Rose-Anne, Marouillat Sylviane, Brulard Céline, Danel-Brunaud Véronique, Camdessanche Jean-Philippe, Blasco Helene, Corcia Philippe, Andres Christian R, Vourc'h Patrick
a UMR INSERM U930 , Université François-Rabelais de Tours , Tours , France.
b Service de neurologie et Pathologie du Mouvement , Centre Hospitalier Universitaire de Lille, Faculté de Médicine, Université de Lille , Lille , France.
Amyotroph Lateral Scler Frontotemporal Degener. 2018 Feb;19(1-2):149-151. doi: 10.1080/21678421.2017.1349152. Epub 2017 Jul 13.
Mutations in the TAR-DNA Binding Protein-43 (TDP-43) encoding the TARDBP gene are present in amyotrophic lateral sclerosis (ALS). TDP-43 is the major component of ubiquitin-positive inclusions in motor neurons in ALS patients. We report here a novel heterozygous missense mutation in TARDBP in an ALS patient presenting a rapid form of ALS. This mutation p.N259S is located within the RNA recognition motif 2 (RRM2) in very close proximity with nucleotides in RNA. It is the first time a mutation was reported in this RRM2 domain of TDP-43. Expression of TDP-43 in neuronal cells NSC-34 and in primary cultures of motor neurons was associated with cytoplasmic TDP-43/ubiquitin positive inclusions. Our findings identified for the first time a mutation in ALS in the RRM2 domain of TDP-43, reinforcing the link between this RNA-binding protein, perturbations in RNA metabolism, disruption in protein homeostasis and ALS.
编码TARDBP基因的TAR-DNA结合蛋白43（TDP-43）发生突变存在于肌萎缩侧索硬化症（ALS）中。TDP-43是ALS患者运动神经元中泛素阳性包涵体的主要成分。我们在此报告一名呈现快速进展型ALS患者的TARDBP基因中存在一种新的杂合错义突变。该突变p.N259S位于RNA识别基序2（RRM2）内，与RNA中的核苷酸非常接近。这是首次在TDP-43的该RRM2结构域中报道突变。TDP-43在神经细胞NSC-34和运动神经元原代培养物中的表达与细胞质中TDP-43/泛素阳性包涵体相关。我们的研究结果首次在ALS中鉴定出TDP-43的RRM2结构域中的突变，加强了这种RNA结合蛋白、RNA代谢紊乱、蛋白质稳态破坏与ALS之间的联系。
