Predictive Modeling Provides Insight into the Clinical Heterogeneity Associated with Loss-of-function Mutations

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes that complete the first step of protein translation: ligation of amino acids to cognate tRNAs. Genes encoding ARSs have been implicated in myriad dominant and recessive phenotypes, the latter often affecting multiple tissues but with frequent involvement of the central and peripheral nervous system, liver, and lungs. Threonyl-tRNA synthetase () encodes the enzyme that ligates threonine to tRNA in the cytoplasm. To date, variants have been implicated in a recessive brittle hair phenotype. To better understand -related recessive phenotypes, we engineered three missense mutations predicted to cause a loss-of-function effect and studied these variants in yeast and worm models. This revealed two loss-of-function mutations, including one hypomorphic allele (R433H). We next used R433H to study the effects of partial loss of function in a compound heterozygous mouse model (R433H/null). This model presents with phenotypes reminiscent of patients with variants and with distinct lung and skin defects. This study expands the potential clinical heterogeneity of -related recessive disease, which should guide future clinical and genetic evaluations of patient populations.