TY  - JOUR
A1  - Schuch, Luise A.
A1  - Forstner, Maria
A1  - Rapp, Christina K.
A1  - Li, Yang
A1  - Smith, Desiree E. C.
A1  - Mendes, Marisa I.
A1  - Delhommel, Florent
A1  - Sattler, Michael
A1  - Emiralioğlu, Nagehan
A1  - Taskiran, Ekim Z.
A1  - Orhan, Diclehan
A1  - Kiper, Nural
A1  - Rohlfs, Meino
A1  - Jeske, Tim
A1  - Hastreiter, Maximilian
A1  - Gerstlauer, Michael
A1  - Torrent‐Vernetta, Alba
A1  - Moreno‐Galdó, Antonio
A1  - Kammer, Birgit
A1  - Brasch, Frank
A1  - Reu‐Hofer, Simone
A1  - Griese, Matthias
T1  - FARS1‐related disorders caused by bi‐allelic mutations in cytosolic phenylalanyl‐tRNA synthetase genes: Look beyond the lungs!
JF  - Clinical Genetics
N2  - 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.
KW  - aminoacyl‐tRNA synthetases
KW  - cholesterol pneumonitis
KW  - FARS1
KW  - children´s interstitial lung disease (chILD) lipoid pneumonia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238827
VL  - 99
IS  - 6
SP  - 789
EP  - 801
ER  -