Alternative titles; symbols
HGNC Approved Gene Symbol: DARS2
SNOMEDCT: 703537008, 735421004;
Cytogenetic location: 1q25.1 Genomic coordinates (GRCh38) : 1:173,824,673-173,858,546 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q25.1 | Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation | 611105 | Autosomal recessive | 3 |
By searching a database for tRNA synthetases, Bonnefond et al. (2005) identified DARS2, which they called MT-ASPRS. The deduced 645-amino acid protein has a 47-amino acid mitochondrial targeting signal, resulting in a mature protein of 598 amino acids. DARS2 contains conserved residues involved in ATP binding, tRNA binding, and aspartic acid recognition, as well as catalytic site motifs characteristic of amino acid tRNA synthetases.
Bonnefond et al. (2005) found that recombinant DARS2 aminoacylated purified E. coli tRNA-asp and in vitro transcribed human mitochondrial tRNA-asp (MTTD; 590015). Gel-filtration chromatography showed that recombinant DARS2 formed dimers.
Bonnefond et al. (2005) determined that the DARS2 gene contains 17 exons and spans 32.5 kb.
Stumpf (2022) mapped the DARS2 gene to chromosome 1q25.1 based on an alignment of the DARS2 sequence (GenBank BC045173) with the genomic sequence (GRCh38).
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105) was defined by van der Knaap et al. (2003) on the basis of the highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy. Affected individuals develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. Scheper et al. (2007) sequenced genes in the candidate region on chromosome 1 linked to LBSL and identified compound heterozygous mutations in the DARS2 gene in affected individuals from all 30 families studied. Enzyme activities of mutant proteins were decreased. Surprisingly, activities of mitochondrial complexes from fibroblasts and lymphoblasts derived from affected individuals were normal, as determined by different assays. LBSL was the first example of a disorder caused by mutations in a gene encoding a mitochondrial aminoacetyl-tRNA synthetase. On the other hand, mutations in genes encoding mitochondrial tRNAs had been found in several human diseases.
In the study of Scheper et al. (2007), almost all participants with LBSL were found to carry 1 mutation involving a stretch of T and C residues just upstream of exon 3 (610956.0001). In 400 control chromosomes, Scheper et al. (2007) invariably found either 3 T residues preceding 11 C residues or 4 T residues preceding 10 C residues. In 6 affected individuals, 1 of the C residues was altered, whereas 22 other affected individuals had 1 allele with only 2 T residues preceding the C stretch. Such changes were predicted to affect splicing of exon 3, leading to a frameshift and truncation of the protein. cDNA analysis confirmed the presence of this frameshift variant, although in a low concentration, probably as a result of nonsense-mediated decay of the mRNA.
Isohanni et al. (2010) found that all 8 patients with LBSL were compound heterozygous for mutations in the DARS2 gene, suggesting that homozygosity for a DARS2 mutation may be lethal in humans.
Miyake et al. (2011) reported 3 Japanese sibs, born of consanguineous parents, with a severe form of LBSL due to a homozygous mutation in the DARS2 gene (610956.0012). Miyake et al. (2011) noted that homozygosity for pathogenic mutations in the DARS2 gene had not previously been reported.
In a German woman with a mild form of LBSL, Synofzik et al. (2011) identified a homozygous missense mutation in the DARS gene (610956.0013). The unaffected parents were heterozygous for the mutation.
Van Berge et al. (2014) reviewed mutations in the DARS2 gene in 120 patients with LBSL. Overall, 60 different mutations were identified, which were located throughout the gene. One hundred and sixteen patients had compound heterozygous mutations and 4 had homozygous mutations. Ninety-four percent (113/120) of the patients were heterozygous for a mutation in the polypyrimidine tract in intron 2, which is just upstream of exon 3. Thirteen different mutations were identified in this region, with 228-20_-21delTTinsC (610956.0001) as the most common, in 88 patients. Mutations in the polypyrimidine tract in intron 2 were identified in only compound heterozygous state. Van Berge et al. (2014) also measured aspartyl-synthetase activity in lymphoblasts from 4 patients with LBSL and all showed a significant loss of activity compared to controls.
Exclusion Studies
Isohanni et al. (2010) found no association between variation in the DARS2 gene among 321 patients with multiple sclerosis (MS; 126200).
Rumyantseva et al. (2020) created a Purkinje cell (PC)-specific knockout Dars2 mouse model and observed that the animals developed a motor impairment phenotype at around 15 weeks of age. At that time the mice also displayed a 50% decrease in PC numbers. PCs in the knockout mice showed strong mitochondrial respiratory chain dysfunction characterized by diminished cytochrome C oxidase and increased succinate dehydrogenase, measures of complex IV and complex II activities. The loss of PCs was accompanied by an increase in activated microglia and hypertrophic Bergmann glia, both indicators of neuroinflammation.
Almost all of the 28 unrelated patients with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105) studied by Scheper et al. (2007) were compound heterozygous for a mutation involving a stretch of T and C residues just upstream of exon 3, designated 228-20_-21delTTinsC. The mutation was predicted to lead to frameshift and premature termination (Arg76SerfsTer5). A variety of mutations were partnered with this indel mutation: L626V (610956.0002) in 1 of the original patients from the Netherlands, R263X (610956.0003) in a patient from Belgium, R263Q (610956.0004) in sibs of German/Kazakhstani extraction, C152F (610956.0005) in patients from Russia, Canada, Italy, and Germany, M134_K165del due to splice site mutation 492+2T-C (610956.0006), S45G (610956.0007) in a patient from Portugal, and R179H (610956.0008) in patients from the Netherlands and Norway.
Isohanni et al. (2010) determined that the frequency of this mutation was 1 in 95 among Finnish controls.
For discussion of the leu626-to-val (L626V) mutation in the DARS2 gene that was found in compound heterozygous state in a patient with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105) by Scheper et al. (2007), see 610956.0001.
The L626V substitution results from a 1875C-G transversion in exon 3 of the DARS2 gene.
For discussion of the arg263-to-ter (R263X) mutation in the DARS2 gene that was found in compound heterozygous state in a patient with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105) by Scheper et al. (2007), see 610956.0001.
The R263X substitution results from a 787C-T transition in exon 9.
For discussion of the arg263-to-gln (R263Q) mutation in the DARS2 gene that was found in compound heterozygous state in sibs with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105) by Scheper et al. (2007), see 610956.0001.
The R263Q substitution results from a 788G-A transition in exon 9.
For discussion of the cys152-to-phe (C152F) mutation in the DARS2 gene that was found in compound heterozygous state in patients with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105) by Scheper et al. (2007), see 610956.0001.
The C152F substitution results from a 455G-T transversion in exon 5.
For discussion of the splice site mutation in the DARS2 gene (492+2T-C) that was found in compound heterozygous state in patients with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105) by Scheper et al. (2007), see 610956.0001.
This splice site mutation results in exon skipping without a frameshift (met134_lys165del).
Isohanni et al. (2010) identified the 492+2T-C splice site mutation as a founder mutation in the Finnish population. Seven patients of Finnish origin with LBSL were compound heterozygous for this mutation and the indel mutation (610956.0001). The carrier frequency of the 492+2T-C mutation among controls was 1 in 380.
For discussion of the ser45-to-gly (S45G) mutation in the DARS2 gene that was found in compound heterozygous state in a patient with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105) by Scheper et al. (2007), see 610956.0001.
The S45G substitution results from a 133A-G transition in exon 2.
In patients with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105) from the Netherlands, Germany, and Norway, Scheper et al. (2007) identified compound heterozygosity for the arg179-to-his (R179H) mutation in the DARS2 gene. In sibs from Norway, it was combined with the Arg76SerfsTer5 mutation (610956.0001); in a patient from the Netherlands, it was combined with the nonsense mutation E425X (610956.0009).
For discussion of the glu425-to-ter (E425X) mutation in the DARS2 gene that was found in compound heterozygous state in patients with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105) by Scheper et al. (2007), see 610956.0008.
The E425X substitution results from a 1273G-T transversion in exon 13.
In a Belgian patient with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105), Scheper et al. (2007) found compound heterozygosity for 2 missense mutations in the DARS2 gene: L613F, brought about by a 1837C-T transition in exon 17, and L626Q (610956.0011).
For discussion of the leu626-to-gln (L626Q) mutation in the DARS2 gene that was found in compound heterozygous state in a patient with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105) by Scheper et al. (2007), see 610956.0010.
The L626Q substitution results from a 1876T-A transversion in exon 17.
In 3 Japanese sibs, born of consanguineous parents, with a severe form of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105), Miyake et al. (2011) identified a homozygous T-to-A transversion 22 basepairs upstream of exon 3 of the DARS2 gene. Each unaffected parent was heterozygous for the mutation, which was not found in 395 controls. RT-PCR analysis of patient lymphoblastoid cells showed a fragment lacking all of exon 3. Wildtype DARS2 mRNA transcript and protein was significantly decreased in patient cells. The 21-year-old proband developed truncal ataxia at age 3 years, followed by nystagmus, slurred speech, tremor, spasticity, and mental retardation; he could speak only 1 or 2 words. His 2 sibs, who showed onset before age 12 months, died in childhood of respiratory disease. Brain imaging showed leukoencephalopathy of the cerebrum, cerebellum, brainstem, and spinal cord. Miyake et al. (2011) noted that homozygosity for pathogenic mutations in the DARS2 gene had not previously been reported.
In a 25-year-old German woman with a mild form of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105), Synofzik et al. (2011) identified a homozygous 1825C-T transition in exon 17 of the DARS2 gene, resulting in an arg609-to-trp (R609W) substitution in a highly conserved residue in mammals. Each unaffected parent was heterozygous for the mutation, which was not found in 338 controls. Functional analysis was not performed. She presented with paroxysmal exercise-induced gait ataxia that first occurred up to 5 times a day and lasted for a few seconds to 5 minutes, but increased in frequency over a few years. Other features included mild distal deficits in position and vibration sense, mild leg spasticity, and hyperreflexia, but she never had permanent cerebellar ataxia or gait spasticity. Serum lactate was intermittently increased, and brain MRI showed T2 hyperintense lesions in the cerebellar white matter, deep cerebral white matter, and periventricular region, with some involvement of the pyramidal tracts and dorsal columns. Treatment with acetazolamide resulted in significantly decreased frequency of the attacks. The findings indicated that this disorder can have a milder phenotype and even present with episodic ataxia.
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]
Isohanni, P., Linnankivi, T., Buzkova, J., Lonnqvist, T., Pihko, H., Valanne, L., Tienari, P. J., Elovaara, I., Pirttila, T., Reunanen, M., Koivisto, K., Marjavaara, S., Suomalainen, A. DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis. J. Med. Genet. 47: 66-70, 2010. [PubMed: 19592391] [Full Text: https://doi.org/10.1136/jmg.2009.068221]
Miyake, N., Yamashita, S., Kurosawa, K., Miyatake, S., Tsurusaki, Y., Doi, H., Saitsu, H., Matsumoto, N. A novel homozygous mutation of DARS2 may cause a severe LBSL variant. (Letter) Clin. Genet. 80: 293-296, 2011. [PubMed: 21815884] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01644.x]
Rumyantseva, A., Motori, E., Trifunovic, A. DARS2 is indispensable for Purkinje cell survival and protects against cerebellar ataxia. Hum. Molec. Genet. 29: 2845-2854, 2020. [PubMed: 32766765] [Full Text: https://doi.org/10.1093/hmg/ddaa176]
Scheper, G. C., van der Klok, T., van Andel, R. J., van Berkel, C. G. M., Sissler, M., Smet, J., Muravina, T. I., Serkov, S. V., Uziel, G., Bugiani, M., Schiffmann, R., Krageloh-Mann, I., Smeitink, J. A. M., Florentz, C., Van Coster, R., Pronk, J. C., van der Knaap, M. S. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nature Genet. 39: 534-539, 2007. [PubMed: 17384640] [Full Text: https://doi.org/10.1038/ng2013]
Stumpf, A. M. Personal Communication. Baltimore, Md. 08/30/2022.
Synofzik, M., Schicks, J., Lindig, T., Biskup, S., Schmidt, T., Hansel, J., Lehmann-Horn, F., Schols, L. Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation. (Letter) J. Med. Genet. 48: 713-715, 2011. [PubMed: 21749991] [Full Text: https://doi.org/10.1136/jmg.2011.090282]
van Berge, L., Hamilton, E. M., Linnankivi, T., Uziel, G., Steenweg, M. E., Isohanni, P., Wolf, N. I., Krageloh-Mann, I., Brautaset, N. J., Andrews, P. I., de Jong, B. A., al Ghamdi, M., and 11 others. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy. Brain 137: 1019-29, 2014. [PubMed: 24566671] [Full Text: https://doi.org/10.1093/brain/awu026]
van der Knaap, M. S., van der Voorn, P., Barkhof, F., Van Coster, R., Krageloh-Mann, I., Feigenbaum, A., Blaser, S., Vles, J. S. H., Rieckmann, P., Pouwels, P. J. W. A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate. Ann. Neurol. 53: 252-258, 2003. [PubMed: 12557294] [Full Text: https://doi.org/10.1002/ana.10456]