A model organism pipeline provides insight into the clinical heterogeneity of TARS1 loss-of-function variants
Rebecca Meyer-Schuman,
Allison R. Cale,
Jennifer A. Pierluissi,
Kira E. Jonatzke,
Young N. Park,
Guy M. Lenk,
Stephanie N. Oprescu,
Marina A. Grachtchouk,
Andrzej A. Dlugosz,
Asim A. Beg,
Miriam H. Meisler,
Anthony Antonellis
Affiliations
Rebecca Meyer-Schuman
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
Allison R. Cale
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
Jennifer A. Pierluissi
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
Kira E. Jonatzke
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
Young N. Park
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
Guy M. Lenk
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
Stephanie N. Oprescu
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
Marina A. Grachtchouk
Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
Andrzej A. Dlugosz
Department of Dermatology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
Asim A. Beg
Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA
Miriam H. Meisler
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Neurology, University of Michigan, Ann Arbor, MI, USA
Anthony Antonellis
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Neurology, University of Michigan, Ann Arbor, MI, USA; Corresponding author
Summary: 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 systems, liver, and lungs. Threonyl-tRNA synthetase (TARS1) encodes the enzyme that ligates threonine to tRNATHR in the cytoplasm. To date, TARS1 variants have been implicated in a recessive brittle hair phenotype. To better understand TARS1-related recessive phenotypes, we engineered three TARS1 missense variants at conserved residues and studied these variants in Saccharomyces cerevisiae and Caenorhabditis elegans models. This revealed two loss-of-function variants, including one hypomorphic allele (R433H). We next used R433H to study the effects of partial loss of TARS1 function in a compound heterozygous mouse model (R432H/null). This model presents with phenotypes reminiscent of patients with TARS1 variants and with distinct lung and skin defects. This study expands the potential clinical heterogeneity of TARS1-related recessive disease, which should guide future clinical and genetic evaluations of patient populations.
