Alternative titles; symbols
HGNC Approved Gene Symbol: FARSB
Cytogenetic location: 2q36.1 Genomic coordinates (GRCh38): 2:222,566,899-222,656,092 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q36.1 | Rajab interstitial lung disease with brain calcifications 1 | 613658 | Autosomal recessive | 3 |
Aminoacyl-tRNA synthetases are enzymes that charge tRNAs with specific amino acids. Cytoplasmic phenylalanine-tRNA synthetase is a heterodimer consisting of a catalytic alpha subunit, FARSA (602918), and a regulatory beta subunit, FARSB (Rodova et al., 1999).
By database analysis, RT-PCR using embryonic kidney cell RNA, and screening a fetal kidney cDNA library, Rodova et al. (1999) cloned FARSB. The 589-amino acid protein has a predicted molecular mass of 66 kD. Sequence alignment of FARSB orthologs from multiple species showed conservation of DNA-binding domains and suggested the heterodimer of FARSB and FARSA form a 4-helix bundle interface similar to that seen in Thermus thermophilus. Human FARSB is approximately 200 amino acids shorter than its prokaryotic homologs and does not contain the RNP domain that binds to anticodons. Northern blot analysis detected a 2.4-kb FARSB transcript in heart, brain, placenta, skeletal muscle, kidney, and pancreas. FARSB expression was stronger in malignant cell lines compared to normal tissue lines.
Using differential display and Northern blot analysis, Zhou et al. (1999) identified murine Farsb as a gene downregulated during suberoylanilide hydroxamic acid-induced differentiation of erythroleukemia cells. Human FARSB shares 93% amino acid identity with its mouse homolog.
Lo et al. (2014) reported the discovery of a large number of natural catalytic nulls for each human aminoacyl tRNA synthetase. Splicing events retain noncatalytic domains while ablating the catalytic domain to create catalytic nulls with diverse functions. Each synthetase is converted into several new signaling proteins with biologic activities 'orthogonal' to that of the catalytic parent. The recombinant aminoacyl tRNA synthetase variants had specific biologic activities across a spectrum of cell-based assays: about 46% across all species affect transcriptional regulation, 22% cell differentiation, 10% immunomodulation, 10% cytoprotection, and 4% each for proliferation, adipogenesis/cholesterol transport, and inflammatory response. Lo et al. (2014) identified in-frame splice variants of cytoplasmic aminoacyl tRNA synthetases. They identified 4 catalytic domain-retained splice variants for PheRSb.
Rodova et al. (1999) showed that COS-7 cells transfected with FARSB and FARSA increased phenylalanine charging of tRNA, whereas transfection of FARSB alone caused a decrease in activity of the endogenous heterodimeric enzyme.
Using database analysis, Zhou et al. (1999) mapped the FARSB gene to chromosome 2 near the PAX3 gene (606597).
In a boy with Rajab interstitial lung disease with brain calcifications (RILDBC1; 613658), resulting in death at age 32 months, Antonellis et al. (2018) identified compound heterozygous mutations in the FARSB gene (609690.0001 and 609690.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed a 97% reduction in the FARSB protein and a 66% reduction in the FARSA (602918) protein compared to controls, suggesting a severe reduction in phenylalanyl-tRNA synthetase activity. Antonellis et al. (2018) postulated a loss-of-function effect.
In affected members of a large consanguineous Omani family with RILDBC1, previously reported by Rajab et al. (2009), Zadjali et al. (2018) identified a homozygous missense mutation in the FARSB gene (E285K; 609690.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed that the FARSB mutant protein was expressed at normal levels. Additional functional studies were not performed, but molecular modeling suggested that the mutation occurs in a domain involved in editing activity.
In 5 patients from 4 unrelated families with RILDBC1, Xu et al. (2018) identified biallelic mutations in the FARSB gene (see, e.g., 609690.0004-609690.0008). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Analysis of cells derived from 1 patient, who carried a missense and a splice site mutation (609690.0004 and 609690.0005), showed decreased protein levels of FARSB and FARSA, but overall protein synthesis was not impaired, suggesting that the disorder results from a different mechanism. Functional studies and studies of patient cells were not performed for the other identified variants, all of which were missense, but molecular modeling predicted that they would affect protein structure.
In a boy with Rajab interstitial lung disease with brain calcifications (RILDBC1; 613658), resulting in death at age 32 months, Antonellis et al. (2018) identified compound heterozygous mutations in the FARSB gene: a c.767C-T transition (c.767C-T, NM_005687.4), resulting in a thr256-to-met (T256M) substitution at a conserved residue in the editing domain, and a c.1486delCinsAA mutation (609690.0002), predicted to result in a frameshift and premature termination (His496LysfsTer14). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. In the gnomAD database, the T256M variant was found at a low frequency in heterozygous state (12 of 276,122 alleles), whereas the frameshift mutation was not found. Western blot analysis of patient cells showed a 97% reduction in the FARSB protein and a 66% reduction in the FARSA (602918) protein compared to controls, suggesting a severe reduction in phenylalanyl-tRNA synthetase activity. Antonellis et al. (2018) postulated a loss-of-function effect.
For discussion of the c.1486delCinsAA mutation (c.1486delCinsAA, NM_005687.4) in the FARSB gene, predicted to result in a frameshift and premature termination (His496LysfsTer14), that was found in compound heterozygous state in a patient with Rajab interstitial lung disease with brain calcifications (RILDBC1; 613658) by Antonellis et al. (2018), see 609690.0001.
In affected members of a large consanguineous Omani family with Rajab interstitial lung disease with brain calcifications (RILDBC1; 613658), previously reported by Rajab et al. (2009), Zadjali et al. (2018) identified a homozygous c.853G-A transition (c.853G-A, NM_005687.4) in the FARSB gene, resulting in a glu285-to-lys (E285K) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database. Western blot analysis of patient cells showed that the FARSB mutant protein was expressed at normal levels. Additional functional studies were not performed, but molecular modeling suggesting that the mutation occurs in a domain involved in editing activity.
In 2 sibs (family 1) with Rajab interstitial lung disease with brain calcifications (RILDBC1; 613658), Xu et al. (2018) identified compound heterozygous mutations in the FARSB gene: a c.914G-A transition (c.914G-A, NM_005687.4), resulting in an arg305-to-gln (R305Q) substitution at a highly conserved residue, and a G-to-A transition in intron 9 (c.848+1G-A; 609690.0005), resulting in a splice site alteration. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Each was found at a low frequency in the gnomAD database (less than 0.001%). Analysis of patient cells showed about 50% FARSB protein levels compared to controls, suggesting that the splice site mutation likely leads to nonsense-mediated mRNA decay and a loss of function. Molecular modeling predicted that the missense mutation may have a structural impact on the protein. Additional studies on patient cells showed decreased protein levels of FARSB and FARSA (602918), but overall protein synthesis was not impaired, suggesting that the disorder results from a different mechanism.
For discussion of the G-to-A transition in intron 9 (c.848+1G-A, NM_005687.4) of the FARSB gene, resulting in a splice site alteration, that was found in compound heterozygous state in 2 sibs with Rajab interstitial lung disease with brain calcifications (RILDBC1; 613658) by Xu et al. (2018), see 609690.0004.
In a boy (patient 3 from family 2) with Rajab interstitial lung disease with brain calcifications (RILDBC1; 613658), who died at age 8 years, Xu et al. (2018) identified compound heterozygous missense mutations in the FARSB gene: a c.1202G-A transition (c.1202G-A, NM_005687.4), resulting in an arg401-to-gln (R401Q) substitution, and a c.1381A-C transversion, resulting in a thr461-to-pro (T461P; 609690.0007) substitution. An unrelated 10-year-old girl (patient 4 from family 3) with a similar disorder was found to be compound heterozygous for R401Q and a c.755T-C transition, resulting in a phe252-to-ser (F252S; 609690.0008) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families and were not found in the gnomAD database. Functional studies of the variants and studies of patient cells were not performed, but all substitutions occurred at highly conserved residues and molecular modeling predicted that they would have an adverse effect on protein structure.
For discussion of the c.1381A-C transversion (c.1381A-C, NM_005687.4) in the FARSB gene, resulting in a thr461-to-pro (T461P) substitution, that was found in compound heterozygous state in a patient with Rajab interstitial lung disease with brain calcifications (RILDBC1; 613658) by Xu et al. (2018), see 609690.0006.
For discussion of the c.755T-C transition (c.755T-C, NM_005687.4) in the FARSB gene, resulting in a phe252-to-ser (F252S) substitution, that was found in compound heterozygous state in a patient with Rajab interstitial lung disease with brain calcifications (RILDBC1; 613658) by Xu et al. (2018), see 609690.0006.
Antonellis, A., Oprescu, S. N., Griffin, L. B., Heider, A., Amalfitano, A., Innis, J. W. Compound heterozygosity for loss-of-function FARSB variants in a patient with classic features of recessive aminoacyl-tRNA synthetase-related disease. Hum. Mutat. 39: 834-840, 2018. [PubMed: 29573043] [Full Text: https://doi.org/10.1002/humu.23424]
Lo, W.-S., Gardiner, E., Xu, Z., Lau, C.-F., Wang, F., Zhou, J. J., Mendlein, J. D., Nangle, L. A., Chiang, K. P., Yang, X.-L., Au, K.-F., Wong, W. H., Guo, M., Zhang, M., Schimmel, P. Human tRNA synthetase catalytic nulls with diverse functions. Science 345: 328-332, 2014. [PubMed: 25035493] [Full Text: https://doi.org/10.1126/science.1252943]
Rajab, A., Aldinger, K. A., El-Shirbini, H. A., Dobyns, W. B., Ross, M. E. Recessive developmental delay, small stature, microcephaly and brain calcifications with locus on chromosome 2. Am. J. Med. Genet. 149A: 129-137, 2009. [PubMed: 19161147] [Full Text: https://doi.org/10.1002/ajmg.a.32630]
Rodova, M., Ankilova, V., Safro, M. G. Human phenylalanyl-tRNA synthetase: cloning, characterization of the deduced amino acid sequences in terms of the structural domains and coordinately regulated expression of the alpha and beta subunits in chronic myeloid leukemia cells. Biochem. Biophys. Res. Commun. 255: 765-773, 1999. [PubMed: 10049785] [Full Text: https://doi.org/10.1006/bbrc.1999.0141]
Xu, Z., Lo, W.-S., Beck, D. B., Schuch, L. A., Olahova, M., Kopajtich, R., Chong, Y. E., Alston, C. L., Seidl, E., Zhai, L., Lau, C.-F., Timchak, D., and 21 others. Bi-allelic mutations in phe-tRNA synthetase associated with a multi-system pulmonary disease support non-translational function. Am. J. Hum. Genet. 103: 100-114, 2018. [PubMed: 29979980] [Full Text: https://doi.org/10.1016/j.ajhg.2018.06.006]
Zadjali, F., Al-Yahyaee, A., Al-Nabhani, M., Al-Mubaihsi, S., Gujjar, A., Raniga, S., Al-Maawali, A. Homozygosity for FARSB mutation leads to phe-tRNA synthetase-related disease of growth restriction, brain calcification and interstitial lung disease. Hum. Mutat. 39: 1355-1359, 2018. [PubMed: 30014610] [Full Text: https://doi.org/10.1002/humu.23595]
Zhou, X., Richon, V. M., Ngo, L., Rifkind, R. A., Marks, P. A. Cloning of the cDNA encoding phenylalanyl tRNA synthetase regulatory alpha-subunit-like protein whose expression is down-regulated during differentiation. Gene 233: 13-19, 1999. [PubMed: 10375616] [Full Text: https://doi.org/10.1016/s0378-1119(99)00170-5]