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

Commun Biol. 2020 Jan 20;3(1):33. doi: 10.1038/s42003-020-0755-1.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution*
  • Amyotrophic Lateral Sclerosis / diagnosis
  • Amyotrophic Lateral Sclerosis / etiology*
  • Amyotrophic Lateral Sclerosis / metabolism
  • CRISPR-Cas Systems
  • Clustered Regularly Interspaced Short Palindromic Repeats*
  • Copper-Transporting ATPases / genetics*
  • Copper-Transporting ATPases / metabolism
  • DNA Mutational Analysis
  • Gene Editing*
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Male
  • Mutation*
  • Neurons / metabolism
  • RNA, Guide, CRISPR-Cas Systems
  • Whole Genome Sequencing

Substances

  • RNA, Guide, CRISPR-Cas Systems
  • ATP7A protein, human
  • Copper-Transporting ATPases