FARS1-related disorders caused by bi-allelic mutations in cytosolic phenylalanyl-tRNA synthetase genes: Look beyond the lungs!

Luise A. Schuch, Maria Forstner, Christina K. Rapp, Yang Li, Desiree E. C. Smith, Marisa I. Mendes, Florent Delhommel, Michael Sattler, Nagehan Emiralioğlu, Ekim Z. Taskiran, Diclehan Orhan, Nural Kiper, Meino Rohlfs, Tim Jeske, Maximilian Hastreiter, Michael Gerstlauer, Alba Torrent-Vernetta, Antonio Moreno-Galdó, Birgit Kammer, Frank BraschSimone Reu-Hofer, Matthias Griese*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Aminoacyl-tRNA synthetases (ARSs) catalyze the first step of protein biosynthesis (canonical function) and have additional (non-canonical) functions outside of translation. Bi-allelic pathogenic variants in genes encoding ARSs are associated with various recessive mitochondrial and multisystem disorders. We describe here a multisystem clinical phenotype based on bi-allelic mutations in the two genes (FARSA, FARSB) encoding distinct subunits for tetrameric cytosolic phenylalanyl-tRNA synthetase (FARS1). Interstitial lung disease with cholesterol pneumonitis on histology emerged as an early characteristic feature and significantly determined disease burden. Additional clinical characteristics of the patients included neurological findings, liver dysfunction, and connective tissue, muscular and vascular abnormalities. Structural modeling of newly identified missense mutations in the alpha subunit of FARS1, FARSA, showed exclusive mapping to the enzyme's conserved catalytic domain. Patient-derived mutant cells displayed compromised aminoacylation activity in two cases, while remaining unaffected in another. Collectively, these findings expand current knowledge about the human ARS disease spectrum and support a loss of canonical and non-canonical function in FARS1-associated recessive disease.
Original languageEnglish
Pages (from-to)789-801
JournalClinical Genetics
Issue number6
Publication statusPublished - 1 Jun 2021

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