FARSA mutations mimic phenylalanyl‐tRNA synthetase deficiency caused by FARSB defects

Abstract

Pathogenic variants in genes encoding aminoacyl‐tRNA synthetases cause numerous disorders characterized by involvement of neurons, muscles, lungs and liver. Recently, biallelic FARSB defects have been shown to cause severe growth restriction with combined brain, liver and lung involvement (Rajab interstitial lung disease [ILD] with brain calcifications). Herein, for the first time, we present a patient with similar condition associated with biallelic mutations in FARSA (NM_004461.3: c.766T>C:p.Phe256Leu and c.1230C>A:p.Asn410Lys). Both detected FARSA variants are ultrarare and predicted to be damaging by in silico programs. Furthermore, they are both located in the active site of phenylalanyl‐tRNA synthetase (PheRS) with Asn410Lys directly affecting a residue forming the wall of the phenylalanine‐binding pocket. Clinical features shared between our patient and the FARSB syndrome include ILD with cholesterol pneumonitis, growth delay, hypotonia, brain calcifications with cysts and liver dysfunction. Our findings indicate that a disease similar to a syndrome associated with FARSB defects can also be caused by biallelic FARSA mutations. These findings are consistent with molecular structure of PheRS which is a tetramer including both FARSA and FARSB proteins.

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

“…Six subjects with predicted disease-causing variants in FARSA and FARSB were retrieved, one was published independently. 10 Patients and families gave their written informed consent to participate in the chILD-EU consultation and diagnosis program. All human subject research was in accordance with current ethical standards and approved by the Ethics Committee of the University of Munich, Germany (EK 111-13, EK 20-329).…”

“…To investigate the impact of both these and previously reported variants 10 on FARS1 structure and function, we aligned T. thermophilus tRNA Phe (PDB: 2IY5) with the crystal structure of human FARS1 (PDB: 3L4G) (Figure 5(B)). In this model, three residues affected by the missense mutations potentially interfere directly with the catalytic activity, due to their proximity to the active site: E418D, N410K, and F256L.…”

“…Whereas 11 individuals presenting with bi-allelic mutations in FARSB are described, 9,12,13 information on FARSArelated disease is rare and comes from a single case report describing a patient with mutations in FARSA and features of interstitial lung disease, cerebral and skeletal abnormalities, hypotonia, and liver dysfunction. 10 Here, we report three unrelated individuals with identified bi-allelic variants in FARSA (MIM: 602918), and two unrelated individuals presenting biallelic variants in the gene encoding the beta subunit, FARSB (MIM: 609690).…”

“…More than 60 disorders are associated with mutations in ARS genes and, depending on their individual genotype, follow both dominant or recessive inheritance patterns. [4][5][6][7][8][9][10] Cytosolic phenylalanyl-tRNA synthetase (FARS1) ranks among the most complex of the ARSs with a hetero-tetrameric structure, consisting of two FARS alpha (FARSA) and two FARS beta (FARSB) subunits. 11 The hypothesis that both genes may be associated with a similar multisystemic human disease, including features of interstitial lung disease, liver disease, neurological manifestations, and growth restriction (MIM: 619013, 613 658), needs further support.…”

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

“…Mutations in cytoplasmic ARS-encoding genes cause peripheral nervous system degeneration resulting in Charcot-Marie-Tooth neuropathies (GARS1 and AARS1 (MIM: 123859), and TARS1 (MIM: 187790), with subsequent partial loss of the ARS protein, have been linked to neurodevelopmental phenotypes. [10][11][12][13][14] Modes of inheritance can be dominant or recessive; in cases such as AARS1, YARS1 (MIM: 603623), MARS1 (MIM: 156560), HARS1 (MIM: 142810), and GARS1, both patterns can occur. 6 The loss of function associated with mutations in ARSs is attributed to decreased aminoacylation efficiency or misfolding, causing protein instability with lower steady-state levels.…”