Alternative titles; symbols
HGNC Approved Gene Symbol: FARS2
SNOMEDCT: 1187506008, 778065005;
Cytogenetic location: 6p25.1 Genomic coordinates (GRCh38): 6:5,249,934-5,771,583 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p25.1 | Combined oxidative phosphorylation deficiency 14 | 614946 | Autosomal recessive | 3 |
| Spastic paraplegia 77, autosomal recessive | 617046 | Autosomal recessive | 3 |
Aminoacyl-tRNA synthetases are enzymes that catalyze attachment of amino acids to their cognate tRNAs. Phenylalanyl-tRNA synthetase (PheRS) is a member of the class II aminoacyl-tRNA synthetases (Bullard et al., 1999).
By screening a human EST database with consensus sequences derived from the conserved regions of the alpha and beta subunits of bacterial PheRS, Bullard et al. (1999) identified 2 partial FARS2 clones. Sequence analysis determined that 1 clone was a truncated form of the other and that human FARS2 consisted of a single polypeptide chain. The deduced 451-amino acid FARS2 protein has a predicted molecular mass of 49.6 kD and an N-terminal mitochondrial targeting signal. FARS2 shares 42% and 52% amino acid identity with yeast and Drosophila mitochondrial PheRS, respectively, and has no significant homology to the eukaryotic cytoplasmic form (see FARSA; 602918). FARS2 migrated as a 48-kD band by SDS-PAGE, and gel filtration and velocity sedimentation centrifugation analysis determined that FARS2 is active as a monomer.
Yang et al. (2016) found expression of the FARS2 gene in rat Purkinje cells in cerebellum, but not in pyramidal cells of the cerebral cortex or in spinal motor neurons. In the cerebellum, FARS2 colocalized with mitochondrial markers.
By aminoacylation assay analysis with expressed tagged-FARS2 in E. coli, Bullard et al. (1999) showed that FARS2 can charge tRNA with phenylalanine, but at a rate 20- to 30-fold lower than that of yeast cytoplasmic PheRS. By analyzing FARS2 activity under varying concentrations of ATP, they demonstrated that human mitochondrial PheRS requires a high concentration of ATP for maximal activity.
Bonnefond et al. (2005) determined that the FARS2 gene contains 6 exons and spans 403 kb.
Elo et al. (2012) stated that the FARS2 gene contains 7 exons, of which exons 2-7 are protein-coding.
Gross (2018) mapped the FARS2 gene to chromosome 6p25.1 based on an alignment of the FARS2 sequence (GenBank AF097441) with the genomic sequence (GRCh38).
Combined Oxidative Phosphorylation Deficiency 14
In 3 sibs, born of consanguineous Saudi Arabian parents, with combined oxidative phosphorylation deficiency (COXPD14; 614946), Shamseldin et al. (2012) identified a homozygous mutation in the FARS2 gene (Y144C; 611592.0001). The mutation was identified by exome sequencing and confirmed by Sanger sequencing.
By exome sequencing of 2 sibs with combined oxidative phosphorylation deficiency manifest as fatal infantile epileptic mitochondrial encephalopathy, Elo et al. (2012) identified compound heterozygosity for 2 missense mutations in the FARS2 gene (I329T, 611592.0002; D391V, 611592.0003). In vitro functional expression studies indicated that these mutations, and the Y144C mutation reported by Shamseldin et al. (2012), all resulted in impaired aminoacylation function and stability of the protein, causing an overall decrease in tRNA charging capacity. The findings indicated that FARS2 mutations cause a mitochondrial translation disorder. The phenotype in all 3 patients was characterized by infantile onset of a fatal encephalopathy with refractory seizures, lack of psychomotor development, and lactic acidosis.
In a male infant with COXPD14, Chen et al. (2023) identified compound heterozygous mutations in the FARS2 gene (EX2DEL, 611592.0011 and R198L, 611592.0012). Steady state levels of mtPheRS were reduced in patient fibroblasts and complex I activity was mildly reduced. A crystal structure of FARS2 with the R198L mutation suggested that the mutation results in destabilization of the protein's core region. An aminoacylation assay demonstrated that the R198L mutation resulted in reduced tRNA charging activity.
Autosomal Recessive Spastic Paraplegia 77
In 4 sibs, born of consanguineous Chinese parents, with autosomal recessive spastic paraplegia-77 (SPG77; 617046), Yang et al. (2016) identified a homozygous missense mutation in the FARS2 gene (D142Y; 611592.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the mutation resulted in severely impaired enzyme activity compared to wildtype.
In 2 sibs with mitochondrial dysfunction and spastic paraplegia, Vernon et al. (2015) identified compound heterozygous mutations in the FARS2 gene: a missense mutation (R429C; 611592.0006) and an intragenic deletion (611592.0007).
In 2 unrelated patients with mitochondrial dysfunction and spastic paraplegia, Vantroys et al. (2017) identified compound heterozygous mutations in the FARS2 gene (611592.0008-611592.0010). FARS2 catalyzes the charging of the tRNA-phe. Compared to normal control fibroblasts, patient fibroblasts showed a decreased amount of Phe-charged tRNA and a decrease in mitochondrial protein synthesis rate, which affected the assembly of OXPHOS complexes.
In 2 sibs, born of consanguineous Saudi Arabian parents, with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), Shamseldin et al. (2012) identified a homozygous 431A-G transition in the FARS2 gene, resulting in a tyr144-to-cys (Y144C) substitution at a highly conserved residue in the catalytic domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in 114 Saudi controls.
Elo et al. (2012) found that the Y144C mutation occurs in the aminoacylation domain on the interface of the anticodon stem-binding domain and may participate in stabilization of the closed structure. In vitro functional expression studies in E. coli indicated that the mutation resulted in decreased affinity for tRNA, causing a decrease in overall tRNA charging capacity.
In 2 Finnish sibs with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), Elo et al. (2012) identified compound heterozygosity for 2 mutations in the FARS2 gene: a 986T-C transition in exon 5 resulting in an ile329-to-thr (I329T) substitution, and a 1172A-T transversion in exon 6 resulting in an asp391-to-val (D391V; 611592.0003) substitution. Each unaffected parent was heterozygous for 1 of the mutations, neither of which was found in 400 Finnish control chromosomes or in the 1000 Genomes Project database. Both mutations occurred at highly conserved residues. The ile329 residue is part of the ATP-binding site in the aminoacylation domain, whereas asp391 is in the anticodon stem-binding domain. In vitro functional expression studies in E. coli indicated that the I329T mutation resulted in a 4-fold decrease in the catalytic activity of amino acid activation due to a decreased affinity for ATP. The D391V mutation was predicted to result in a decrease in phe binding, causing a decrease in aminoacylation activity. Both mutations also caused decreased stabilization of the proteins, resulting in a decrease in overall charging capacity.
For discussion of the asp391-to-val (D391V) mutation in the FARS2 gene that was found in compound heterozygous state in patients with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946) by Elo et al. (2012), see 611592.0002.
In a 2.5-year-old boy, born of unrelated British Caucasian parents, with a variant of combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), Almalki et al. (2014) identified a maternally inherited heterozygous c.973G-T transversion (c.973G-T, NM_006567.3) in exon 5 of the FARS2 gene, resulting in an asp325-to-tyr (D325Y) substitution at a conserved residue in the catalytic domain that is involved in ATP binding. High resolution array CGH showed that the other allele carried a paternally inherited 88-kb interstitial deletion of chromosome 6p25.1 including the promoter and untranslated exon 1 of FARS2 and the 3-prime exons of the LYRM4 (613311) gene. A missense mutation in the LYRM4 gene (R68L) has been identified in a family with COXPD19 (615595). Analysis of tissues from the patient reported by Almalki et al. (2014) showed an isolated complex IV deficiency in skeletal muscle and myoblasts, but not in fibroblasts. Northern and Western blot analysis of patient skeletal muscle showed decreased levels of FARS2 mRNA and protein, respectively, compared to controls, and in vitro functional expression assays showed that the D325Y mutant protein had no detectable enzyme activity and no detectable ATP binding. However, patient myoblasts did not show impaired synthesis of mitochondrial proteins, and there was not a decrease in mtDNA.
In 4 sibs, born of consanguineous Chinese parents, with autosomal recessive spastic paraplegia-77 (SPG77; 617046), Yang et al. (2016) identified a homozygous c.424G-T transversion (c.424G-T, NM_006567.3) in exon 2 of the FARS2 gene, resulting in an asp142-to-tyr (D142Y) substitution at a highly conserved residue in the catalytic motif of aminoacylation at the interface of the anticodon stem-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 132) or 1000 Genomes Project databases. In vitro functional expression studies in E. coli showed that the mutation resulted in severely impaired enzyme activity compared to wildtype. The aminoacylation activity was impaired at the first aminoacylation step and at the last transfer step.
In 2 sibs with mitochondrial dysfunction and spastic paraplegia (SPG77; 617046), Vernon et al. (2015) identified compound heterozygous mutations in the FARS2 gene: a paternally inherited c.1255C-T transition in exon 7, resulting in an arg419-to-cys (R419C) substitution at a conserved location in the phenylalanyl-RNA synthetase C-terminal domain, and a maternally inherited 116-kb interstitial deletion (nucleotides 5,610,223-5,726,369), including all of exon 6 and parts of introns 5 and 6. The mutations, which were found by exome sequencing and SNP array, respectively, were confirmed by Sanger sequencing. The missense mutation was not found in 6,500 individuals in the NHBLI Exome Sequencing Project database. Functional studies of the variants were not performed.
For discussion of the 116-kb interstitial deletion in the FARS2 gene that was found in compound heterozygous state in 2 sibs with mitochondrial dysfunction and spastic paraplegia (SPG77; 617046) by Vernon et al. (2015), see 611592.0006.
In 2 unrelated patients with mitochondrial dysfunction and spastic paraplegia (SPG77; 617046), Vantroys et al. (2017) identified compound heterozygous mutations in the FARS2 gene: a c.1082C-T transition (c.1082C-T, NM_006567.4) in exon 6, resulting in a pro361-to-leu (P361L) substitution in the anticodon binding domain, in both probands, combined with a c.461C-T transition in exon 2, resulting in an ala154-to-val (A154V; 611592.0009) substitution in the catalytic domain, in proband 1, and a 3-bp deletion (c.521_523delTGG), resulting in deletion of val174 (611592.0010) in the catalytic domain, in proband 2. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The P361L and A154V had a prevalence of 15/60,675 and 2/60,594, respectively, in the ExAC database, whereas V174del was not found in ExAC. Compared with normal control fibroblasts, patient fibroblasts showed a decreased amount of Phe-charged tRNA and a decrease in mitochondrial protein synthesis rate, which affected the assembly of OXPHOS complexes: complex IV in proband 1 and complex I in proband 2.
For discussion of the c.461C-T transition (c.461C-T, NM_006567.4) in exon 2 of the FARS2 gene, resulting in an ala154-to-val (A154V) substitution, that was found in compound heterozygous state in a patient with spastic paraplegia-77 (SPG77; 617046) by Vantroys et al. (2017), see 611592.0008.
For discussion of the 3-bp deletion (c.521_523delTGG, NM_006567.4) in the FARS2 gene, resulting in a deletion of val174 (V174del), that was found in compound heterozygous state in a patient with spastic paraplegia-77 (SPG77; 617046) by Vantroys et al. (2017), see 611592.0008.
In a male infant with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), Chen et al. (2023) identified compound heterozygous mutations in the FARS2 gene: a deletion of exon 2 (NM_006567.5), the first coding exon, and a c.593G-T transversion, resulting in an arg198-to-leu (R198L; 611592.0012) substitution. The mutations were identified by trio whole-exome sequencing, and the parents were shown to be mutation carriers. The R198L mutation was present in the gnomAD database in 1 of 125,000 alleles and was not present in homozygosity. Steady state levels of mtPheRS were reduced in patient fibroblasts.
For discussion of the c.593G-T transversion (c.593G-T, NM_006567.5) in the FARS2 gene that was found in compound heterozygous state in an infant with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946) by Chen et al. (2023), see 611592.0002.
Almalki, A., Alston, C. L., Parker, A., Simonic, I., Mehta, S. G., He, L., Reza, M., Oliveira, J. M. A., Lightowlers, R. N., McFarland, R., Taylor, R. W., Chrzanowska-Lightowlers, Z. M. A. Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency. Biochim. Biophys. Acta 1842: 56-64, 2014. [PubMed: 24161539] [Full Text: https://doi.org/10.1016/j.bbadis.2013.10.008]
Bonnefond, L., Fender, A., Rudinger-Thirion, J., Giege, R., Florentz, C., Sissler, M. Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS. Biochemistry 44: 4805-4816, 2005. [PubMed: 15779907] [Full Text: https://doi.org/10.1021/bi047527z]
Bullard, J. M., Cai, Y.-C., Demeler, B., Spremulli, L. L. Expression and characterization of a human mitochondrial phenylalanyl-tRNA synthetase. J. Molec. Biol. 288: 567-577, 1999. [PubMed: 10329163] [Full Text: https://doi.org/10.1006/jmbi.1999.2708]
Chen, W., Rehsi, P., Thompson, K., Yeo, M., Stals, K., He, L., Schimmel, P., Chrzanowska-Lightowlers, Z. M. A., Wakeling, E., Taylor, R. W., Kuhle, B. Clinical and molecular characterization of novel FARS2 variants causing neonatal mitochondrial disease. Molec. Genet. Metab. 140: 107657, 2023. [PubMed: 37523899] [Full Text: https://doi.org/10.1016/j.ymgme.2023.107657]
Elo, J. M., Yadavalli, S. S., Euro, L., Isohanni, P., Gotz, A., Carroll, C. J., Valanne, L., Alkuraya, F. S., Uusimaa, J., Paetau, A., Caruso, E. M., Pihko, H., Ibba, M., Tyynismaa, H., Suomalainen, A. Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy. Hum. Molec. Genet. 21: 4521-4529, 2012. [PubMed: 22833457] [Full Text: https://doi.org/10.1093/hmg/dds294]
Gross, M. B. Personal Communication. Baltimore, Md. 2/1/2018.
Shamseldin, H. E., Alshammari, M., Al-Sheddi, T., Salih, M. A., Alkhalidi, H., Kentab, A., Repetto, G. M., Hashem, M., Alkuraya, F. S. Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes. J. Med. Genet. 49: 234-241, 2012. [PubMed: 22499341] [Full Text: https://doi.org/10.1136/jmedgenet-2012-100836]
Vantroys, E., Larson, A., Friederich, M., Knight, K., Swanson, M. A., Powell, C. A., Smet, J., Vergult, S., De Paepe, B., Seneca, S., Roeyers, H., Menten, B., Minczuk, M., Vanlander, A., Van Hove, J., Van Coster, R. New insights into the phenotype of FARS2 deficiency. Molec. Genet. Metab. 122: 172-181, 2017. [PubMed: 29126765] [Full Text: https://doi.org/10.1016/j.ymgme.2017.10.004]
Vernon, H. J., McClellan, R., Batista, D. A. S., Naidu, S. Mutations in FARS2 and non-fatal mitochondrial dysfunction in two siblings. Am. J. Med. Genet. 167A: 1147-1151, 2015. [PubMed: 25851414] [Full Text: https://doi.org/10.1002/ajmg.a.36993]
Yang, Y., Liu, W., Fang, Z., Shi, J., Che, F., He, C., Yao, L., Wang, E., Wu, Y. A newly identified missense mutation in FARS2 causes autosomal-recessive spastic paraplegia. Hum. Mutat. 37: 165-169, 2016. [PubMed: 26553276] [Full Text: https://doi.org/10.1002/humu.22930]