Recessive AARS1 variants perturb human and mouse development.

Humans with pathogenic loss of function alanyl-tRNA synthetase 1 (AARS1) variants have a range of congenital brain phenotypes, including a high prevalence of microcephaly. The molecular mechanisms for this are unclear but zebrafish mutants in aars1 have reduced neurogenesis and increased apoptosis. Here, we report two individuals with compound heterozygous AARS1 variants. We created two mouse models to study the role of Aars1 in embryonic brain development. We provide evidence from these mouse models and in vitro splicing assays that both human AARS1 alleles are pathogenic. Mice homozygous for either a missense allele or an indel allele are both lethal very early in embryonic development. Aars1G80S/WT heterozygous animals show reduced Purkinje cell immunoreactivity at 8 months of age but no gross morphological cerebellar phenotypes or impaired performance in a motor coordination assay. We conclude these are pathogenic alleles in AARS1 but lethality in mice preclude a detailed study of neural development.