Newly identified human aminoacyl‐ tRNA synthetase complex interacting multifunctional protein 2 ( AIMP2 ) loss‐of‐function mutations cause neurodevelopmental defects linked to cell death in a zebrafish model

Aminoacyl-tRNA synthetase complex interacting multifunctional protein 2 (AIMP2) is a component of the eukaryote-specific multisynthetase complex (MSC), a macromolecular assembly of eight aminoacyl-tRNA synthetases (ARS) and three scaffolding components known as aminoacyl-tRNA synthetase interacting multifunctional proteins (AIMP1-3). Recent studies show that bi-allelic mutations in AIMP2 cause a neurodevelopmental syndrome that overlaps phenotypically with disorders caused by recessive ARS mutations. In this work, we further characterize AIMP2 mutations in two patients with severe neurodevelopmental disorders, including one previously unreported compound heterozygous patient. We show patient-derived fibroblast AIMP2 mutations cause decreased protein expression, attenuation of protein synthesis, and dysregulation of the MSC component, methionyl-tRNA synthetase (MARS1). CRISPR-mediated disruption of aimp2 in zebrafish led to increased cell death and atrophy in the developing brain, further supporting a link between AIMP2 dysfunction and neurodevelopmental defects. We tested anticodon engineered suppressor tRNAs on expression of disease-associated nonsense mutations and found that they dramatically increase protein expression of AIMP2 variants. Together, these data demonstrate that AIMP2 depletion leads to neurodevelopmental dysfunction in both human and zebrafish, and suggest that therapies such as anticodon engineered suppressor tRNAs could improve patient outcomes.