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AARS2
Identifiers
Aliases	AARS2, AARSL, COXPD8, LKENP, MT-ALARS, MTALARS, alanyl-tRNA synthetase 2, mitochondrial
External IDs	OMIM: 612035; MGI: 2681839; HomoloGene: 56897; GeneCards: AARS2; OMA:AARS2 - orthologs
Gene location (Human) Chr. Chromosome 6 (human) Band 6p21.1 Start 44,298,731 bp End 44,313,347 bp
Gene location (Mouse) Chr. Chromosome 17 (mouse) Band 17|17 B3 Start 45,817,767 bp End 45,831,769 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in tendon of biceps brachii pancreatic ductal cell nipple skin of arm cerebellar vermis vena cava mucosa of ileum endothelial cell vulva pylorus Top expressed in otolith organ utricle hand seminiferous tubule spermatocyte epiblast foot quadriceps femoris muscle right kidney knee joint More reference expression data BioGPS n/a
Gene ontology Molecular function aminoacyl-tRNA ligase activity nucleotide binding amino acid binding tRNA binding metal ion binding ligase activity RNA binding nucleic acid binding alanine-tRNA ligase activity ATP binding zinc ion binding aminoacyl-tRNA editing activity Cellular component cytoplasm mitochondrion Biological process tRNA aminoacylation protein biosynthesis alanyl-tRNA aminoacylation tRNA modification mitochondrial alanyl-tRNA aminoacylation mitochondrial respiratory chain complex assembly aminoacyl-tRNA metabolism involved in translational fidelity Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 57505 224805 Ensembl ENSG00000124608 ENSMUSG00000023938 UniProt Q5JTZ9 Q14CH7 RefSeq (mRNA) NM_020745 NM_198608 NM_001358000 RefSeq (protein) NP_065796 NP_941010 NP_001344929 Location (UCSC) Chr 6: 44.3 – 44.31 Mb Chr 17: 45.82 – 45.83 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Alanyl—tRNA synthetase, mitochondrial, also known as alanine—tRNA ligase (AlaRS) or alanyl—tRNA synthetase 2 (AARS2), is an enzyme that in humans is encoded by the AARS2 gene.

Clinical relevance

Gene changes in the AARS2 gene result in infantile mitochondrial cardiomyopathies. Progressive leukoencephalopathy with Ovarian Failure (LKENP).

Function

The AARS2 gene provides instructions for producing alanyl-tRNA synthetase 2, which is localized to mitochondria. This enzyme plays a critical role in the fidelity of mitochondrial protein translation by charging tRNAs with the correct amino acid (alanine). Proper mitochondrial protein synthesis is essential for the assembly and function of the oxidative phosphorylation system, which drives ATP production. Dysregulation of this process can disrupt cellular energy homeostasis and lead to a cascade of pathophysiological effects.

Pathogenic Variants and Associated Disorders

Leukoencephalopathy

AARS2-related leukodystrophy causes dementia, upper motor neuron signs and ataxia.

Ovarian Failure

A subset of patients with AARS2 gene changes has been reported to exhibit premature ovarian insufficiency (POI), indicating a potential link between mitochondrial dysfunction and reproductive health. POI is often an early or predominant manifestation in affected women.

Cardiac and Multisystem Disorders

Emerging reports describe AARS2 variants in patients with cardiomyopathy, including dilated cardiomyopathy, alongside neurological and systemic manifestations. These findings underscore the pleiotropic effects of AARS2 mutations on multiple organ systems.

Genetics

The AARS2 gene is located on chromosome 6 (6p21.1) and comprises 20 exons. Mutations reported include missense, nonsense, and splice-site variants, as well as deletions. Pathogenic mutations often lead to impaired enzyme function, resulting in defective mitochondrial protein synthesis. The inheritance pattern is autosomal recessive, requiring both alleles to carry mutations for the disorder to manifest.

Diagnosis

Clinical Presentation

Patients may present with a combination of neurological symptoms, including ataxia, spasticity, and cognitive decline. In cases of LBSL, characteristic MRI findings are critical for diagnosis.

Genetic Testing

Diagnostic confirmation involves genetic testing to identify pathogenic variants in AARS2. Whole exome sequencing (WES) or targeted gene panels for mitochondrial disorders are commonly used.

Biochemical Tests

Elevated lactate levels in the cerebrospinal fluid or through magnetic resonance spectroscopy (MRS) can provide supportive evidence of mitochondrial dysfunction.

Management

Currently, there are no specific treatments targeting AARS2-related disorders. Management is primarily supportive and symptom-based:

Neurological Symptoms: Physical therapy, occupational therapy, and medications for spasticity (e.g., baclofen) may improve quality of life.

Premature Ovarian Insufficiency: Hormone replacement therapy (HRT) and fertility counseling are recommended for affected women.

Cardiac Symptoms: Routine cardiac monitoring and management by a cardiologist are essential in patients with cardiomyopathy.

Research Directions

Mechanistic Studies

Ongoing research aims to understand the molecular mechanisms linking AARS2 mutations to mitochondrial dysfunction. Insights into these pathways could reveal novel therapeutic targets.

Therapeutic Development

Gene therapy, small-molecule chaperones, and mitochondrial-targeted antioxidants are potential avenues under investigation to address mitochondrial disorders, including those involving AARS2.

Resources for Patients and Families

Patient Advocacy Groups

CureARS - a non-profit organization dedicated to spreading awareness, connecting & providing support to affected families and funding research for the ultra-rare Mitochondrial ARS genes.

United Mitochondrial Disease Foundation (UMDF)

MitoAction

The Lily Foundation (United Kingdom) - A charity supporting patients and families affected by mitochondrial diseases.

Alex TLC (United Kingdom) - Advocacy and support for individuals with leukodystrophies, including a dedicated page on AARS2-related conditions.

AEPMI - Asociación Española de Pacientes con Enfermedades Mitocondriales (Spain) - Spanish organization providing resources and support for mitochondrial disease patients.

Genetic Counseling

Families affected by AARS2-related disorders are encouraged to seek genetic counseling for reproductive planning and understanding inheritance patterns.

Clinical Trials

A search on ClinicalTrials.gov can provide updates on ongoing research and experimental treatments for mitochondrial diseases.

Support Networks

Online communities and forums for mitochondrial disease patients and caregivers offer emotional support and shared experiences.

References

van Berge L, et al. (2014). "AARS2 mutations: A common cause of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL)." Brain.

Isohanni P, et al. (2019). "Novel phenotypes associated with AARS2 mutations." Journal of Inherited Metabolic Disease.

Sofou K, et al. (2015). "AARS2-related mitochondrial cardiomyopathy: Expanding the clinical spectrum." European Journal of Medical Genetics.

Online Mendelian Inheritance in Man (OMIM). AARS2. OMIM Entry.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000124608 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000023938 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: alanyl-tRNA synthetase 2".
6. Bonnefond L, Fender A, Rudinger-Thirion J, Giegé R, Florentz C, Sissler M (March 2005). "Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS". Biochemistry. 44 (12): 4805–16. doi:10.1021/bi047527z. PMID 15779907.
7. Götz A, Tyynismaa H, Euro L, Ellonen P, Hyötyläinen T, Ojala T, Hämäläinen RH, Tommiska J, Raivio T, Oresic M, Karikoski R, Tammela O, Simola KO, Paetau A, Tyni T, Suomalainen A (May 2011). "Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy". American Journal of Human Genetics. 88 (5): 635–42. doi:10.1016/j.ajhg.2011.04.006. PMC 3146718. PMID 21549344.

Further reading

• Nakayama M, Kikuno R, Ohara O (November 2002). "Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs". Genome Research. 12 (11): 1773–84. doi:10.1101/gr.406902. PMC 187542. PMID 12421765.
• Nagase T, Ishikawa K, Kikuno R, Hirosawa M, Nomura N, Ohara O (October 1999). "Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 6 (5): 337–45. doi:10.1093/dnares/6.5.337. PMID 10574462.
• Hendrickson SL, Lautenberger JA, Chinn LW, Malasky M, Sezgin E, Kingsley LA, Goedert JJ, Kirk GD, Gomperts ED, Buchbinder SP, Troyer JL, O'Brien SJ (2010). "Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression". PLOS ONE. 5 (9): e12862. Bibcode:2010PLoSO...512862H. doi:10.1371/journal.pone.0012862. PMC 2943476. PMID 20877624.
• Bonnefond L, Fender A, Rudinger-Thirion J, Giegé R, Florentz C, Sissler M (March 2005). "Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS". Biochemistry. 44 (12): 4805–16. doi:10.1021/bi047527z. PMID 15779907.
• Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ (March 2000). "Shotgun sequencing of the human transcriptome with ORF expressed sequence tags". Proceedings of the National Academy of Sciences of the United States of America. 97 (7): 3491–6. Bibcode:2000PNAS...97.3491D. doi:10.1073/pnas.97.7.3491. PMC 16267. PMID 10737800.
• Fan Y, Han J, Yang Y (2022). "Novel mitochondrial alanyl-tRNA synthetase 2 (AARS2) heterozygous mutations in a Chinese patient with adult-onset leukoencephalopathy". BMC Neurology. 22. Retrieved 2025-01-05.

• Lynch DS, Zhang WJ, Lakshmanan R, Kinsella JA, Uzun GA, Karbay M, Tufekcioglu Z, Hanagasi H, Burke G, Foulds N, et al. (2016). "Analysis of Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia". JAMA Neurology. 73 (12): 1433–1439. doi:10.1001/jamaneurol.2016.2766.

• Götz A, Tyynismaa H, Euro L, Ellonen P, Hyötyläinen T, Ojala T, Hämäläinen RH, Tommiska J, Raivio T, Oresic M, et al. (2011). "Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy". American Journal of Human Genetics. 88 (5): 635–642.

• Wang X, Wang Q, Tang H, Chen B, Dong X, Niu S, Li S, Shi Y, Shan W, Zhang Z (2019). "Novel Alanyl-tRNA Synthetase 2 Pathogenic Variants in Leukodystrophies". Frontiers in Neurology. 10.

• Kiraly-Borri C, Jevon G, Ji W, Jeffries L, Ricciardi JL, Konstantino M, Ackerman KG, Lakhani SA (2019). "Siblings with lethal primary pulmonary hypoplasia and compound heterozygous variants in the AARS2 gene: further delineation of the phenotypic spectrum". Cold Spring Harbor Molecular Case Studies. 5 (3).

• De Michele G, Galatolo D, Lieto M, Maione L, Cocozza S, Santorelli FM, Filla A (2020). "New AARS2 Mutations in Two Siblings With Tremor, Downbeat Nystagmus, and Primary Amenorrhea: A Benign Phenotype Without Leukoencephalopathy". Movement Disorders Clinical Practice. 7 (6): 684–687. doi:10.1002/mdc3.12958. PMC 7328423.

• Euro L, Konovalova S, Asin-Cayuela J, Tulinius M, Griffin H, Horvath R, Taylor RW, Chinnery PF, Schara U, Thorburn DR, et al. (2015). "Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation". Frontiers in Genetics. 6.

• Fine AS, Nemeth CL, Kaufman ML, Fatemi A (2019). "Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination". Journal of Neurodevelopmental Disorders. 11.

• Götz A, Suomalainen A (2012). "Mitochondrial alanyl-tRNA synthetase (AARS2) mutations: adult leukoencephalopathy and infantile cardiomyopathy". Journal of Internal Medicine. 271 (6): 595–597. doi:10.1111/j.1365-2796.2012.02568.x.

• Dallabona C, Diodato D, Kevelam SH, Haack TB, Wong LJ, Salomons GS, Agosta F, Mariotti C, Smits BW, Rodenburg RJ, et al. (2014). "Novel (ovario) leukodystrophy related to AARS2 mutations". Neurology. 82 (23): 2063–2071. doi:10.1212/WNL.0000000000000415.

See also

• Aminoacyl tRNA synthetase

External links

• AARS2 human gene location in the UCSC Genome Browser.
• AARS2 human gene details in the UCSC Genome Browser.
• CureARS non profit organisation supporting families affected by ARS mutations, including AARS2.

• Biology

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