CRISPR-mediated gene correction links the ATP7A M1311V mutations with amyotrophic lateral sclerosis pathogenesis in one individual.
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.
Digital Object Identifier (DOI)
Yun, Yeomin; Hong, Sung-Ah; Kim, Ka-Kyung; Baek, Daye; Lee, Dongsu; Londhe, Ashwini M; Lee, Minhyung; Yu, Jihyeon; McEachin, Zachary T; Bassell, Gary J; Bowser, Robert; Hales, Chadwick M; Cho, Sung-Rae; Kim, Janghwan; Pae, Ae Nim; Cheong, Eunji; Kim, Sangwoo; Boulis, Nicholas M; Bae, Sangsu; and Ha, Yoon, "CRISPR-mediated gene correction links the ATP7A M1311V mutations with amyotrophic lateral sclerosis pathogenesis in one individual." (2020). Translational Neuroscience. 475.