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.
Bibliographical noteFunding Information:
The authors appreciate the family for their participation in this study. The authors thank J.M. Lee and C. Justin Lee at Center for Cognition and Sociality, Institute for Basic Science for providing valuable comments. This work was supported by the Gluck Family Foundation. 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.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
- Medicine (miscellaneous)