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

• Type of Material: Article
• Authors: Yeomin Yun, Yonsei University; Sung-Ah Hong, Hanyang University; Ka-Kyung Kim, Yonsei University; Daye Baek, Yonsei University; Dongsu Lee, Yonsei University; Ashwini M. Londhe, Korea Institute of Science and Technology; Minhyung Lee, Korea Research Institute of Bioscience and Biotechnology; Jihyeon Yu, Hanyang University; Zachary T. McEachin, Emory University; Gary Bassell, Emory University; Robert Bowser, Barrow Neurological Institute; Chadwick Hales, Emory University; Sung-Rae Cho, Yonsei University; Janghwan Kim, Korea Research Institute of Bioscience and Biotechnology; Ae Nim Pae, Korea Institute of Science and Technology; Eunji Cheong, Yonsei University; Sangwoo Kim, Yonsei University; Nicholas Boulis, Emory University; Sangsu Bae, Hanyang University; Yoon Ha, Yonsei University
• Language: English
• Date: 2020-01-20
• Publisher: NATURE PUBLISHING GROUP
• Publication Version: Final Published Version
• Copyright Statement: © 2020, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s42003-020-0755-1
• Title of Journal or Parent Work: COMMUNICATIONS BIOLOGY
• Volume: 3
• Issue: 1
• Start Page: 33
• End Page: 33
• Grant/Funding Information: This work was also supported by National Research Foundation of Korea (NRF) Grants (no. 2018M3A9H3022412 to S.B., no. 2015M3A9C7030128 to J.K., no. 2013R1A1A2062110 to K.K.K., no. 2015R1D1A1A02059821 to Y.H.) and by a grant from the Korea Healthcare technology R&D Project (HI16C1012) to S.B and by a faculty research grant from the Yonsei University College of Medicine (6-2018-0161) to Y.H.; This work was supported by the Gluck Family Foundation.
• Keywords: ASSOCIATION; Science & Technology - Other Topics; NEURODEGENERATION; MECHANISMS; Life Sciences & Biomedicine - Other Topics; Science & Technology; VARIANTS; GENOMICS; P-TYPE ATPASES; ALS; PHENOTYPE; Multidisciplinary Sciences; Biology; TOOL; Life Sciences & Biomedicine
• Research Categories: Biology, Genetics; Biology, Neuroscience

Abstract

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.