Biology:AARS2
 Generic protein structure example |
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.[1][2]
Clinical relevance
Gene changes in the AARS2 gene result in infantile mitochondrial cardiomyopathies.[3] 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)
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
- ↑ "Entrez Gene: alanyl-tRNA synthetase 2". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=57505.
- ↑ "Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS". Biochemistry 44 (12): 4805–16. March 2005. doi:10.1021/bi047527z. PMID 15779907.
- ↑ "Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy". American Journal of Human Genetics 88 (5): 635–42. May 2011. doi:10.1016/j.ajhg.2011.04.006. PMID 21549344.
Further reading
- "Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs". Genome Research 12 (11): 1773–84. November 2002. doi:10.1101/gr.406902. PMID 12421765.
- "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. October 1999. doi:10.1093/dnares/6.5.337. PMID 10574462.
- "Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression". PLOS ONE 5 (9). 2010. doi:10.1371/journal.pone.0012862. PMID 20877624. Bibcode: 2010PLoSO...512862H.
- "Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS". Biochemistry 44 (12): 4805–16. March 2005. doi:10.1021/bi047527z. PMID 15779907.
- "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. March 2000. doi:10.1073/pnas.97.7.3491. PMID 10737800. Bibcode: 2000PNAS...97.3491D.
- "Novel mitochondrial alanyl-tRNA synthetase 2 (AARS2) heterozygous mutations in a Chinese patient with adult-onset leukoencephalopathy". BMC Neurology 22 (1). 2022. doi:10.1186/s12883-022-02720-3. PMID 35676634.
- "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. 2016. doi:10.1001/jamaneurol.2016.2229. PMID 27749956. https://jamanetwork.com/journals/jamaneurology/fullarticle/2569686.
- "Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy". American Journal of Human Genetics 88 (5): 635–642. 2011. doi:10.1016/j.ajhg.2011.04.006. PMID 21549344.
- "Novel Alanyl-tRNA Synthetase 2 Pathogenic Variants in Leukodystrophies". Frontiers in Neurology 10. 2019. doi:10.3389/fneur.2019.01321. PMID 31920941.
- "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). 2019. doi:10.1101/mcs.a003699. PMID 30819764.
- "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. 2020. doi:10.1002/mdc3.12958. PMID 32626814.
- "Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation". Frontiers in Genetics 6: 21. 2015. doi:10.3389/fgene.2015.00021. PMID 25705216.
- "Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination". Journal of Neurodevelopmental Disorders 11 (1). 2019. doi:10.1186/s11689-019-9292-y. PMID 31839000.
- "Mitochondrial alanyl-tRNA synthetase (AARS2) mutations: adult leukoencephalopathy and infantile cardiomyopathy". Journal of Internal Medicine 271 (6): 595–597. 2012. doi:10.1111/j.1365-2796.2012.02568.x. PMID 22759240.
- "Novel (ovario) leukodystrophy related to AARS2 mutations". Neurology 82 (23): 2063–2071. 2014. doi:10.1212/WNL.0000000000000415. PMID 24808023.
See also
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.
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