CRISPR-mediated gene correction links the ATP7A M1311V mutations with amyotrophic lateral sclerosis pathogenesis in one individual.,Communications Biology

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CRISPR-mediated gene correction links the ATP7A M1311V mutations with amyotrophic lateral sclerosis pathogenesis in one individual.
Communications Biology ( IF 5.2 ) Pub Date : 2020-01-20 , DOI: 10.1038/s42003-020-0755-1
Yeomin Yun _{1,

2} , Sung-Ah Hong _{3,

4} , Ka-Kyung Kim ₅ , Daye Baek _{1,

2} , Dongsu Lee ₆ , Ashwini M Londhe _{7,

8} , Minhyung Lee _{9,

10} , Jihyeon Yu ₃ , Zachary T McEachin ₁₁ , Gary J Bassell _{11,

12} , Robert Bowser ₁₃ , Chadwick M Hales ₁₄ , Sung-Rae Cho _{2,

15} , Janghwan Kim _{9,

10} , Ae Nim Pae _{7,

8} , Eunji Cheong ₆ , Sangwoo Kim ₅ , Nicholas M Boulis ₁₆ , Sangsu Bae _{3,

4} , Yoon Ha _{1,

2}

Affiliation

Department of Neurosurgery, Spine & Spinal Cord Institute, College of Medicine, Yonsei University, Seoul, 03722, South Korea.
Brain Korea 21 PLUS Project for Medical Science, College of Medicine, Yonsei University, Seoul, 03722, South Korea.
Department of Chemistry, Hanyang University, Seoul, 04763, South Korea.
Research Institute for Natural Sciences, Hanyang University, Seoul, 04763, South Korea.
Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, 03722, South Korea.
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, South Korea.
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul, 130-650, South Korea.
Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, South Korea.
Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, South Korea.
Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, South Korea.
Laboratory of Translational Cell Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Department of Cell Biology, Emory University, Atlanta, GA, 30322, USA.
Department of Neurobiology, Barrow Neurological Institute and St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA.
Department of Neurology, Emory University, Atlanta, GA, 30322, USA.
Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, 03722, South Korea.
Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, 30322, USA.

Amyotrophic lateral sclerosis (ALS) is a severe disease causing motor neuron death, but a complete cure has not been developed and related genes have not been defined in more than 80% of cases. Here we compared whole genome sequencing results from a male ALS patient and his healthy parents to identify relevant variants, and chose one variant in the X-linked ATP7A gene, M1311V, as a strong disease-linked candidate after profound examination. Although this variant is not rare in the Ashkenazi Jewish population according to results in the genome aggregation database (gnomAD), CRISPR-mediated gene correction of this mutation in patient-derived and re-differentiated motor neurons drastically rescued neuronal activities and functions. These results suggest that the ATP7A M1311V mutation has a potential responsibility for ALS in this patient and might be a potential therapeutic target, revealed here by a personalized medicine strategy.

中文翻译：

CRISPR 介导的基因校正将 ATP7A M1311V 突变与一个个体的肌萎缩侧索硬化症发病机制联系起来。

肌萎缩性脊髓侧索硬化症（ALS）是一种导致运动神经元死亡的严重疾病，但目前尚未开发出完全治愈的方法，并且在超过 80% 的病例中相关基因尚未确定。在这里，我们比较了一名男性 ALS 患者及其健康父母的全基因组测序结果，以识别相关变异，并经过深入检查后选择 X 连锁 ATP7A 基因中的一个变异 M1311V 作为与疾病强相关的候选变异。尽管根据基因组聚合数据库 (gnomAD) 的结果，这种变异在德系犹太人中并不罕见，但 CRISPR 介导的对源自患者和重新分化的运动神经元中的这种突变的基因校正极大地挽救了神经元的活动和功能。这些结果表明 ATP7A M1311V 突变对该患者的 ALS 具有潜在的作用，并且可能是一个潜在的治疗靶点，这是通过个性化医疗策略揭示的。

更新日期：2020-01-21

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