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

Yeomin Yun, Sung Ah Hong, Ka Kyung Kim, Daye Baek, Dongsu Lee, Ashwini M. Londhe, Minhyung Lee, Jihyeon Yu, Zachary T. McEachin, Gary J. Bassell, Robert Bowser, Chadwick M. Hales, Sung Rae Cho, Janghwan Kim, Ae Nim Pae, Eunji Cheong, Sangwoo Kim, Nicholas M. Boulis, Sangsu Bae, Yoon Ha

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number33
JournalCommunications Biology
Volume3
Issue number1
DOIs
Publication statusPublished - 2020 Dec 1

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Medicine (miscellaneous)

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    Yun, Y., Hong, S. A., Kim, K. K., Baek, D., Lee, D., Londhe, A. M., Lee, M., Yu, J., McEachin, Z. T., Bassell, G. J., Bowser, R., Hales, C. M., Cho, S. R., Kim, J., Pae, A. N., Cheong, E., Kim, S., Boulis, N. M., Bae, S., & Ha, Y. (2020). CRISPR-mediated gene correction links the ATP7A M1311V mutations with amyotrophic lateral sclerosis pathogenesis in one individual. Communications Biology, 3(1), [33]. https://doi.org/10.1038/s42003-020-0755-1