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.
Highlights
IntroductionAmyotrophic 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
We found that the ATP7A-M1311V-induced neural stem cells (iNSCs) population showed no difference in the proliferation rate compared to the control iNSCs, but showed lower cell viability, lower lysyl oxidase (LOX) activity, and elevated reactive oxygen species (ROS) under basal cell conditions, similar to the results from the experiments with induced pluripotent stem (iPS) cells described above (Supplementary Fig. 10), supporting our conclusion that the ATP7A M1311V mutation has a potential responsibility for Amyotrophic lateral sclerosis (ALS)
In this study, we revealed that the X-linked ATP7A M1311V mutation has a potential responsibility for ALS in one male ALS patient by comparing whole genome sequencing (WGS) results with his healthy parents
Summary
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. 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 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. We combined the whole genome sequencing (WGS) and CRISPR-Cas[9] mediated gene editing technologies to identify disease linked mutations in an ALS patient, as well as to verify the disease relevance of the mutation in patient-derived iPS cells, suggesting the strategy of personalized medicine
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