Alternative titles; symbols
HGNC Approved Gene Symbol: VARS2
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:30,914,238-30,926,459 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.33 | Combined oxidative phosphorylation deficiency 20 | 615917 | Autosomal recessive | 3 |
The VARS2 gene encodes mitochondrial valyl-tRNA (Val-tRNA) synthetase, which is involved in mitochondrial translation (summary by Diodato et al., 2014).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2001) cloned VARS2, which they designated KIAA1885. The deduced 1,098-amino acid protein shares a high degree of similarity with human valyl-tRNA synthetase (VARS; 192150). RT-PCR ELISA detected nearly uniform VARS2 expression in all adult and fetal tissues and specific adult brain regions examined.
By searching databases for aminoacyl-tRNA synthetases containing a mitochondrial targeting sequence, Bonnefond et al. (2005) identified VARS2, which they called mitochondrial VALRS. The deduced 993-amino acid protein has an N-terminal mitochondrial targeting signal with a predicted cleavage site after residue 29. VARS2 has characteristics of a class I mitochondrial aminoacyl-tRNA synthetase, including a classical Rossmann fold.
Bonnefond et al. (2005) determined that the VARS2 gene contains 30 exons and spans 11.4 kb.
By genomic sequence analysis, Nagase et al. (2001) and Bonnefond et al. (2005) mapped the VARS2 gene to chromosome 6.
In a British boy with combined oxidative phosphorylation deficiency-20 (COXPD20; 615917), Taylor et al. (2014) identified compound heterozygous missense mutations in the VARS2 gene (612802.0001 and 612802.0002). The mutations were found by whole-exome sequencing. The patient was part of a study of 53 patients with mitochondrial respiratory chain complex deficiencies who underwent whole-exome sequencing. Functional studies of the variants were not performed.
In a boy with a mitochondrial encephalomyopathy, Diodato et al. (2014) identified a homozygous missense mutation in the VARS2 gene (T367I; 612802.0003). Patient cells showed decreased amounts of Val-tRNA, and introduction of wildtype VARS2 rescued the mitochondrial biochemical defects. Studies in yeast also confirmed the deleterious effect of the mutation.
In a Greek infant with COXPD20, Baertling et al. (2017) identified compound heterozygous mutations in the VARS2 gene: T367I and R201W (612802.0004). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations. Studies in patient fibroblasts showed a decrease in VARS2 protein levels compared to controls.
In 13 patients from 9 unrelated families segregating COXPD20, Bruni et al. (2018) identified homozygous or compound heterozygous mutations in the VARS2 gene (see, e.g., 612802.0003, 612802.0005-612802.0010). The mutations, which were identified by whole-exome sequencing or next-generation sequencing of a targeted mitochondrial panel in the probands, were confirmed by Sanger sequencing. VARS2 protein levels were reduced in 2 patients (patients 4 and 5).
In 2 unrelated girls from Sardinia with COXPD20, Begliuomini et al. (2019) identified homozygosity for the T367I mutation in the VARS2 gene. The mutations were identified by whole-exome sequencing or sequencing of a targeted mitochondrial panel and confirmed by Sanger sequencing. A skeletal muscle biopsy in 1 patient showed partial reduction of respiratory chain complexes I and III.
In a British boy with combined oxidative phosphorylation deficiency-20 (COXPD20; 615917), Taylor et al. (2014) identified compound heterozygous mutations in the VARS gene: a c.1135G-A transition, resulting in an ala379-to-thr (A379T) substitution, and a c.1877C-A transversion, resulting in an ala626-to-asp (A626D; 612802.0002) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the dbSNP (build 137), Exome Sequencing Project, or 1000 Genomes Project databases, or in 238 in-house controls. Functional studies of the variants were not performed.
For discussion of the ala626-to-asp (A626D) mutation in the VARS2 gene that was found in compound heterozygous state in a patient with combined oxidative phosphorylation deficiency-20 (COXPD20; 615917) by Taylor et al. (2014), see 612802.0001.
In a boy with combined oxidative phosphorylation deficiency-20 (COXPD20; 615917) manifest as mitochondrial encephalomyopathy, Diodato et al. (2014) identified a homozygous c.1100C-T transition in the VARS2 gene, resulting in a thr367-to-ile (T367I) 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 and was not present in public databases, including dbSNP and the Exome Sequencing Project. Western blot analysis of patient fibroblasts showed decreased levels of the VARS2 protein, suggesting partial instability, and charged tRNA-Val was also decreased compared to controls. Studies of the homologous mutant in yeast were consistent with decreased respiration, possibly due to interruption of the substrate-binding site by the substitution. Introduction of wildtype VARS2 rescued the defective mitochondrial respiration observed in patient fibroblasts.
In a Greek infant with COXPD20, Baertling et al. (2017) identified compound heterozygous mutations in the VARS2 gene: T367I and a c.601C-T transition resulting in an arg201-to-trp (R201W; 612802.0004) substitution. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations. In the ExAC database, the T367I variant had a frequency of 0.0024% and the R201W variant a frequency of 0.0025%. Studies in patient fibroblasts showed decreased VARS2 protein levels and decreased oxygen consumption.
In a girl (P1) from a Polish family (family 1) and in 3 sibs (P11, P12, P13) from an Afghan family (family 9) with COXPD20, Bruni et al. (2018) identified homozygosity for the recurrent T367I mutation in the VARS2 gene. The mutation occurs in a region important for the interaction of VARS2 with the cognate tRNA. Bruni et al. (2018) also found the T367I variant in compound heterozygous state in 5 additional patients (see, e.g., 612802.0007, 612802.0008, 612802.0009).
In 2 unrelated girls from Sardinia with COXPD20, Begliuomini et al. (2019) identified homozygosity for the T367I mutation in the VARS2 gene. The mutations were identified by whole-exome sequencing or sequencing of a targeted mitochondrial panel and confirmed by Sanger sequencing. The parents of 1 girl were noted to be heterozygous for the mutation. A skeletal muscle biopsy in 1 patient showed partial reduction of respiratory chain complexes I+III.
For discussion of the c.601C-T transition in the VARS2 gene, resulting in an arg201-to-trp (R201W) substitution, that was found in compound heterozygous state in a patient with combined oxidative phosphorylation deficiency-20 (COXPD20; 615917) by Baertling et al. (2017), see 612802.0003.
In 3 patients (P8, P9, P10) from 2 unrelated Mexican families (families 7 and 8) with combined oxidative phosphorylation deficiency-20 (COXPD20; 615917), Bruni et al. (2018) identified homozygosity for a c.1258G-A transition (c.1258G-A, NM_001167734.1) in the VARS2 gene, resulting in an ala420-to-thr (A420T) substitution in a region important for the interaction of VARS2 with the cognate mRNA. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents were heterozygous for the mutation. The A420T variant had a frequency of 0.0312% in the ExAC database. Functional studies were not performed. The patients had infantile-onset hypertrophic cardiomyopathy, elevated plasma lactate, and hypotonia.
In a male infant (P3) from a Jewish family (family 3) with combined oxidative phosphorylation deficiency-20 (COXPD20; 615917), Bruni et al. (2018) identified compound heterozygous mutations in the VARS2 gene: a c.1546G-T transversion (c.1546G-T, NM_001167734.1), resulting in a glu516-to-ter (E516X) substitution, and a c.2239G-A transition, resulting in an ala747-to-thr (A747T; 612802.0008) substitution at a conserved residue in a region important for the interaction of VARS2 with the cognate mRNA. The mutations were identified by whole-exome sequencing. The E516X variant had a frequency of 0.0117%, and the A747T variant a frequency of 0.0009 in the ExAC database. Functional studies were not performed. The patient had infantile-onset pulmonary hypertension, hypertrophic cardiomyopathy, intermittently elevated plasma and urine lactate, and hypertonia of the lower extremities.
In 2 affected sibs (P6 and P7) from a Polish family (family 6) segregating combined oxidative phosphorylation deficiency-20 (COXPD20; 615917), Bruni et al. (2018) identified compound heterozygous mutations in the VARS2 gene: T367I (612907.0003) and a c.1490G-A transition (c.1490G-A, NM_001167734.1) resulting in an arg497-to-his (R497H) substitution. The R497H variant had a frequency of 0.0025% in the ExAC database.
For discussion of the c.2239G-A transition (c.2239G-A, NM_001167734.1) in the VARS2 gene, resulting in an ala747-to-thr (A747T) substitution, that was found in compound heterozygous state in a patient with combined oxidative phosphorylation deficiency-20 (COXPD20; 615917) by Bruni et al. (2018), see 612802.0006.
In an Italian patient (P4) from family 4 with combined oxidative phosphorylation deficiency-20 (COXPD20; 615917), Bruni et al. (2018) identified compound heterozygous mutations in the VARS2 gene: T367I (612802.0003) and a c.1150G-A transition, resulting in an asp384-to-asn (D384N; 612802.0009) substitution at a conserved residue located in a region important for the interaction of VARS2 with the cognate mRNA. The mutations were identified by next-generation sequencing of mitochondrial-associated genes and confirmed by Sanger sequencing. Western blot analysis in patient fibroblasts showed reduced expression of the VARS2 protein. The D384N variant had a frequency of 0.0009% in the ExAC database.
In a Caucasian female (P2) from family 2 with combined oxidative phosphorylation deficiency-20 (COXPD20; 615917), Bruni et al. (2018) identified compound heterozygous mutations in the VARS2 gene: T367I (612802.0003) and a splice site mutation (c.2557-2A-G, NM_001167734.1). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The variant had a frequency of 0.0228% in the ExAC database.
Baertling, F., Alhaddad, B., Seibt, A., Budaeus, S., Meitinger, T., Strom, T. M., Mayatepek, E., Schaper, J., Prokisch, H., Haack, T. B., Distelmaier, F. Neonatal encephalocardiomyopathy caused by mutations in VARS2. Metab. Brain Dis. 32: 267-270, 2017. [PubMed: 27502409] [Full Text: https://doi.org/10.1007/s11011-016-9890-2]
Begliuomini, C., Magli, G., Di Rocco, M., Santorelli, F. M., Cassandrini, D., Nesti, C., Deodato, F., Diodato, D., Casellato, S., Simula, D. M., Dessi, V., Eusebi, A., Carta, A., Sotgiu, S. VARS2-linked mitochondrial encephalopathy: two case reports enlarging the clinical phenotype. BMC Med. Genet. 20: 77, 2019. Note: Electronic Article. [PubMed: 31064326] [Full Text: https://doi.org/10.1186/s12881-019-0798-7]
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]
Bruni, F., Di Meo, I., Bellacchio, E., Webb, B. D., McFarland, R., Chrzanowska-Lightowlers, Z. M. A., He, L., Skorupa, E., Moroni, I., Ardissone, A., Walczak, A., Tyynismaa, H., and 10 others. Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease. Hum. Mutat. 39: 563-578, 2018. [PubMed: 29314548] [Full Text: https://doi.org/10.1002/humu.23398]
Diodato, D., Melchionda, L., Haack, T. B., Dallabona, C., Baruffini, E., Donnini, C., Granata, T., Ragona, F., Balestri, P., Margollicci, M., Lamantea, E., Nasca, A., Powell, C. A., Minczuk, M., Strom, T. M., Meitinger, T., Prokisch, H., Lamperti, C., Zeviani, M., Ghezzi, D. VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies. Hum. Mutat. 35: 983-989, 2014. [PubMed: 24827421] [Full Text: https://doi.org/10.1002/humu.22590]
Nagase, T., Kikuno, R., Ohara, O. Prediction of the coding sequences of unidentified human genes. XXI. The complete sequences of 60 new cDNA clones from brain which code for large proteins. DNA Res. 8: 179-187, 2001. [PubMed: 11572484] [Full Text: https://doi.org/10.1093/dnares/8.4.179]
Taylor, R. W., Pyle, A., Griffin, H., Blakely, E. L., Duff, J., He, L., Smertenko, T., Alston, C. L., Neeve, V. C., Best, A., Yarham, J. W., Kirschner, J., and 17 others. Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA 312: 68-77, 2014. [PubMed: 25058219] [Full Text: https://doi.org/10.1001/jama.2014.7184]