Alternative titles; symbols
HGNC Approved Gene Symbol: VARS1
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:31,777,518-31,795,752 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.33 | Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy | 617802 | Autosomal recessive | 3 |
The VARS gene encodes the cytoplasmic aminoacyl-tRNA synthetase for valine (summary by Friedman et al., 2019).
Hsieh et al. (1991) identified the G7a gene, encoding human valyl-tRNA synthetase, within the class III region of the major histocompatibility complex (MHC). Hsieh and Campbell (1991) cloned a VARS cDNA encoding a deduced 1,265-amino acid protein with a molecular mass of 140,457 Da. Comparison of the amino acid sequence with those in protein databases showed 38 to 48% identity to valyl-tRNA of bacteria and yeast.
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 6 catalytic-null and 1 catalytic domain-retained splice variants for VALRS.
Siekierska et al. (2019) found that the VARS protein localizes predominantly in the endoplasmic reticulum in human fibroblasts.
Hsieh et al. (1991) identified the G7a gene (VARS) in a 680-kb segment of DNA within the class III region of the MHC on chromosome 6p21.3.
In 3 patients from 2 unrelated consanguineous families with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA; 617802), Karaca et al. (2015) identified homozygous missense mutations in the VARS gene (L885F, 192150.0001 and R1058Q, 192150.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed, but Karaca et al. (2015) noted that mutations in other genes involved in various other aminoacyl-tRNA synthetases (see, e.g., DARS, 603084) have been identified in neurologic disorders. The families were part of a cohort of 128 mostly consanguineous families with neurogenetic disorders, often including brain malformations, that underwent whole-exome sequencing.
In a boy, born of unrelated parents of Indian origin, with NDMSCA, Stephen et al. (2018) identified compound heterozygous mutations in the VARS gene (192150.0003 and 192150.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The patient had a brother with a similar phenotype who died at age 12 months; DNA from the affected brother was not available. Studies of patient-derived fibroblasts showed about 50% decreased VARS mRNA, severely decreased VARS protein levels, and about a 4-fold decrease in aminoacylation activity of VARS compared to controls. The findings suggested that the mutations caused a loss of function with a negative impact on protein synthesis and cellular metabolism.
In 7 patients from 5 families with NDMSCA, Friedman et al. (2019) identified homozygous or compound heterozygous mutations in the VARS gene (see, e.g., 192150.0005 and 192150.0006). The mutations, which were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Most were missense mutations, although 1 patient with a very severe phenotype was compound heterozygous for a missense and a nonsense mutation. Fibroblasts derived from several patients with different mutations showed significantly decreased VARS enzymatic activity, about 20%, compared to wildtype, consistent with a partial loss of function.
In 10 patients from 7 unrelated families with NDMSCA, including the 2 families previously reported by Karaca et al. (2015), Siekierska et al. (2019) identified homozygous or compound heterozygous mutations in the VARS gene (see, e.g., 192150.0007-192150.0011). The mutations, which were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. Affected members in all but 1 family carried biallelic missense mutations; 2 sibs in family 3 were compound heterozygous for a frameshift and a missense mutation (192150.0009 and 192150.0010). All missense variants occurred at conserved residues in or close to the catalytic or anticodon-binding domains, and could be broadly categorized into 2 groups based on molecular modeling: one group was predicted to have an adverse effect on protein structure, and the other was predicted to interfere with tRNA binding. Various studies were performed on the missense mutations, including enzymatic activity, yeast complementation studies, and zebrafish rescue. Analysis of cells derived from some patients showed significantly decreased VARS enzymatic activity compared to controls (at least 50%, but usually less than 25% residual activity). Some of the mutant proteins were able to restore growth in yeast complementation studies, but 3 were unable to fully rescue defects in zebrafish with knockdown of the vars gene. The findings overall indicated that the mutations result in a loss-of-function effect, and that VARS is a critical gene for neuronal development.
In wildtype zebrafish, Siekierska et al. (2019) found that vars was strongly and selectively expressed in the developing brain, eye, and other organs during embryogenesis. CRISPR/Cas9-mediated knockdown of the vars gene in zebrafish resulted in increased lethality, loss of posture, abnormal behavior with jerky spasmodic movements, progressive microcephaly with head abnormalities, increased apoptosis in the head, microphthalmia, and pericardial edema. Electrophysiologic studies on mutant fish also showed epileptiform activity.
The assignment of another valyl-tRNA synthetase gene, previously designated VARS1, to chromosome 9 by Walter et al. (1987) was found to be in error.
In 2 sisters, born of consanguineous parents (family HOU1242), with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA; 617802), Karaca et al. (2015) identified a homozygous c.2653C-T transition (c.2653C-T, NM_006295) in the VARS gene, resulting in a leu885-to-phe (L885F) substitution at a conserved residue in the tRNA synthase class I domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. (In the article by Karaca et al. (2015), the nucleotide change is given as c.2653C-T in Table 1, but as c.2655C-T in the text. Karaca (2017) confirmed that c.2653C-T is correct.)
Siekierska et al. (2019) provided follow-up of the family reported by Karaca et al. (2015), noting that the family was of Turkish descent. In vitro studies showed that the L885F variant was able to sustain growth in a yeast complementation study. The variant was not found in the gnomAD database.
In a girl, born of consanguineous parents (family HOU2294), with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA; 617802), Karaca et al. (2015) identified a homozygous c.3173G-A transition (c.3173G-A, NM_006295) in the VARS gene, resulting in an arg1058-to-gln (R1058Q) substitution at a conserved residue in the anticodon-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
Siekierska et al. (2019) provided follow-up of the family reported by Karaca et al. (2015), noting that the family was of Turkish descent. In vitro studies demonstrated that the R1058Q variant was unable to rescue the abnormal phenotype in zebrafish with knockdown of the vars gene, suggesting that it causes a loss of function. The variant was found at a low frequency in the gnomAD database (1.104 x 10(-5)).
In a boy, born of unrelated parents of Indian origin, with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA; 617802), Stephen et al. (2018) identified compound heterozygous mutations in the VARS gene: an A-to-G transition (c.1577-2A-G, NM_006295.2) in intron 11, resulting in a splicing aberration, and a c.3192G-A transition in exon 27, resulting in a met1064-to-ile (M1064I; 192150.0004) substitution at a highly conserved residue in the anticodon-binding domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and were not found in the ExAC or gnomAD databases. The patient had a brother with a similar disorder who died at age 12 months; DNA from the affected brother was not available. The splice site mutation was predicted to result in the skipping of exon 13, resulting in a frameshift and premature termination (Asp526AlafsTer22), which would abolish both the tRNA synthetase and anticodon-binding domains. Analysis of patient cells suggested that the splice site mutation resulted in nonsense-mediated mRNA decay. The M1064I variant was predicted to disturb the anticodon-binding domain and also possibly result in protein instability. Studies of patient-derived fibroblasts showed about 50% decreased VARS mRNA, severely decreased VARS protein levels, and about a 4-fold decrease in aminoacylation activity of VARS compared to controls. The results suggested a negative impact of the mutations on protein synthesis and cellular metabolism.
For discussion of the c.3192G-A transition (c.3192G-A, NM_006295.2) in exon 27 of the VARS gene, resulting in a met1064-to-ile (M1064I) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA; 617802) by Stephen et al. (2018), see 192150.0003.
In a 5-year-old girl, born of consanguineous Egyptian parents (family 2937), with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA; 617802), Friedman et al. (2019) identified a homozygous c.2840G-A transition (c.2840G-A, NM_006295.2) in the VARS gene, resulting in an arg947-to-his (R947H) substitution at a highly conserved residue close to the tRNA-binding site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of patient fibroblasts showed normal levels of the mutant protein, but significantly reduced VARS enzymatic activity compared to controls.
In 3 patients from 2 unrelated consanguineous Egyptian families (3308 and 3439) with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA; 617802), Friedman et al. (2019) identified a homozygous c.3355C-T transition (c.3355C-T, NM_006295.2) in the VARS gene, resulting in an arg1119-to-cys (R1119C) substitution at a highly conserved residue close to the tRNA-binding site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of patient fibroblasts showed normal levels of the mutant protein, but significantly reduced VARS enzymatic activity compared to controls.
In 2 brothers of German descent (family 1) with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA; 617802), Siekierska et al. (2019) identified compound heterozygous missense mutations in the VARS gene: a c.1300C-G transversion (c.1300C-G, NM_006295.2), resulting in a leu434-to-val (L434V) substitution, and a c.2464G-A transition, resulting in a gly822-to-ser (G822S; 192150.0008) substitution. The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The L434V variant was not found in the gnomAD database, whereas G822S was found there at a low frequency (1.66 x 10(-5)). The mutations occurred at conserved residues, and molecular modeling predicted that they would have adverse effects on protein structure. Analysis of patient cells showed decreased VARS enzymatic activity compared to controls. Yeast complementation studies suggested that the G822S variant was a null allele, whereas L434V was able to support yeast growth.
For discussion of the c.2464G-A transition (c.2464G-A, NM_006295.2) in the VARS gene, resulting in a gly822-to-ser (G822S) substitution, that was found in compound heterozygous state in 2 sibs with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA; 617802) by Siekierska et al. (2019), see 192150.0007.
In 2 sibs (family 3) with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA; 617802), Siekierska et al. (2019) identified compound heterozygous mutations in the VARS gene: a 14-bp duplication (c.219_232dup, NM_006295.2), resulting in a frameshift and premature termination (Leu78ArgfsTer35), and a c.2825G-A transition, resulting in an arg942-to-gln (R942Q; 192150.0010) substitution at a conserved residue in the tRNA-binding domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The duplication was found at a low frequency in the gnomAD database (4.274 x 10(-6)), whereas the R942Q variant was not present in gnomAD. Analysis of patient cells indicated that the frameshift allele was subject to nonsense-mediated mRNA decay, and there was a 50% decrease in protein levels. VARS activity in the patient cells was significantly decreased (less than 25%) compared to controls. The R942Q mutant protein showed normal localization to the endoplasmic reticulum.
For discussion of the c.2825G-A transition (c.2825G-A, NM_006295.2) in the VARS gene, resulting in an arg942-to-gln (R942Q) substitution, that was found in compound heterozygous state in 2 sibs with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA; 617802) by Siekierska et al. (2019), see 192150.0009.
In 2 unrelated girls (patients 9 and 10) with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA; 617802), Siekierska et al. (2019) identified a homozygous c.1210C-T transition (c.1210C-T, NM_006295.2) in the VARS gene, resulting in an arg404-to-trp (R404W) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The variant was found at a low frequency in the gnomAD database (8.328 x 10(-6)). Molecular modeling based on T. thermophilus suggested that the mutation may have an effect on protein structure. Patient cells showed a significant loss of VARS enzymatic activity compared to controls. One girl was of German/Jordanian descent, and the other was of Israeli/Arab descent.
Friedman, J., Smith, D. E., Issa, M. Y., Stanley, V., Wang, R., Mendes, M. I., Wright, M. S., Wigby, K., Hildreth, A., Crawford, J. R., Koehler, A. E., Chowdhury, S., and 17 others. Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy. Nature Commun. 10: 707, 2019. Note: Electronic Article. [PubMed: 30755602] [Full Text: https://doi.org/10.1038/s41467-018-07067-3]
Hsieh, S.-L., Campbell, R. D. Evidence that gene G7a in the human major histocompatibility complex encodes valyl-tRNA synthetase. Biochem. J. 278: 809-816, 1991. Note: Erratum: Biochem. J. 281: 879 only, 1992. [PubMed: 1898367] [Full Text: https://doi.org/10.1042/bj2780809]
Hsieh, S.-L., Kendall, E., Milner, C., Cross, S., Cheng, J., Khanna, A., Olaversen, M., Campbell, R. D. Cloning of the human valyl-tRNA synthetase gene and its location in the major histocompatibility complex on chromosome 6. (Abstract) Cytogenet. Cell Genet. 58: 1912 only, 1991.
Karaca, E., Harel, T., Pehlivan, D., Jhangiani, S. N., Gambin, T., Akdemir, Z. C., Gonzaga-Jauregui, C., Erdin, S., Bayram, Y., Campbell, I. M., Hunter, J. V., Atik, M. M., and 52 others. Genes that affect brain structure and function identified by rare variant analyses of mendelian neurologic disease. Neuron 88: 499-513, 2015. [PubMed: 26539891] [Full Text: https://doi.org/10.1016/j.neuron.2015.09.048]
Karaca, E. Personal Communication. Houston, Texas December 9, 2017.
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]
Siekierska, A., Stamberger, H., Deconinck, T., Oprescu, S. N., Partoens, M., Zhang, Y., Sourbron, J., Adriaenssens, E., Mullen, P., Wiencek, P., Hardies, K., Lee, J.-S., and 28 others. Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish. Nature Commun. 10: 708, 2019. Note: Electronic Article. [PubMed: 30755616] [Full Text: https://doi.org/10.1038/s41467-018-07953-w]
Stephen, J., Nampoothiri, S., Banerjee, A., Tolman, N. J., Penninger, J. M., Elling, U., Agu, C. A., Burke, J. D., Devadathan, K., Kannan, R., Huang, Y., Steinbach, P. J., Martinis, S. A., Gahl, W. A., Malicdan, M. C. V. Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy. Hum. Genet. 137: 293-303, 2018. [PubMed: 29691655] [Full Text: https://doi.org/10.1007/s00439-018-1882-3]
Walter, B., Yen, A., Wasmuth, J., Smith, M. Selection of somatic cell hybrids containing human chromosome 9 using a temperature sensitive CHO valyl-t-RNA synthetase mutant. (Abstract) Cytogenet. Cell Genet. 46: 710 only, 1987.