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Schuch, L.A.* ; Forstner, M.* ; Rapp, C.K.* ; Li, Y.* ; Smith, D.E.C.* ; Mendes, M.I.* ; Delhommel, F. ; Sattler, M. ; Emiralioğlu, N.* ; Taskiran, E.Z.* ; Orhan, D.* ; Kiper, N.* ; Rohlfs, M.* ; Jeske, T.* ; Hastreiter, M.* ; Gerstlauer, M.* ; Torrent-Vernetta, A.* ; Moreno-Galdó, A.* ; Kammer, B.* ; Brasch, F.* ; Reu-Hofer, S.* ; Griese, M.*

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

Clin. Genet. 99, 789-801 (2021)
Verlagsversion DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Fars1 ; Farsa ; Farsb ; Aminoacyl-trna Synthetases ; Children´s Interstitial Lung Disease (child) Lipoid Pneumonia ; Cholesterol Pneumonitis
ISSN (print) / ISBN 0009-9163
e-ISSN 1399-0004
Zeitschrift Clinical Genetics
Quellenangaben Band: 99, Heft: 6, Seiten: 789-801 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Förderungen German Center for Lung Research
Deutsches Zentrum für Lungenforschung
ERA-Net for Research on Rare Diseases
E-Rare-3
European Cooperation in Science and Technology
European Molecular Biology Organization
Helmholtz-Gemeinschaft
Spanish Society of Pneumology and Thoracic Surgery
Spanish Society of Pediatric Pulmonology
Deutsche Forschungsgemeinschaft