MARS2

MARS2 encodes mitochondrial methionyl-tRNA synthetase, an essential enzyme that initiates mitochondrial protein synthesis by attaching methionine to its corresponding tRNA. 

Disruption of MARS2 impairs oxidative phosphorylation and is linked to severe neurodegenerative and mitochondrial disorders, including spastic ataxia and Combined OXPHOS Deficiency 25.

What is MARS2 (Methionyl-tRNA Synthetase 2, Mitochondrial)?

MARS2 is a nuclear gene located on chromosome 2q33.1. It encodes the enzyme mitochondrial methionyl-tRNA synthetase 2 (mtMetRS), a key player in mitochondrial protein synthesis. 

The MARS2 protein catalyzes the ATP-dependent attachment of the amino acid methionine to its cognate mitochondrial tRNA^Met, a critical first step in initiating mitochondrial translation. 

As a class I aminoacyl-tRNA synthetase, MARS2 operates within the mitochondrial matrix to support the synthesis of proteins encoded by mitochondrial DNA, many of which are subunits of the oxidative phosphorylation (OXPHOS) system. This process is essential for proper mitochondrial function and cellular energy production via ATP synthesis. 

The protein is a 593-amino acid monomer (~67 kDa) and lacks the zinc-binding and dimerization domains found in some cytosolic synthetases.

When is MARS2 Testing or Research Relevant?

Genetic testing or functional analysis of MARS2 is most relevant in the context of mitochondrial disorders and neurodegenerative syndromes. Two primary conditions associated with MARS2 dysfunction are:

Spastic Ataxia 3

Spastic Ataxia 3 (SPAX3), also known as ARSAL (Spastic Ataxia with Leukoencephalopathy), is an autosomal recessive disorder caused by complex copy number variants (e.g., full or partial duplications and deletions) in the MARS2 gene. 

It typically presents in childhood to adulthood with progressive spasticity in the lower limbs, balance difficulties, cerebellar ataxia, and white matter abnormalities on brain MRI (leukoencephalopathy). Additional features may include hyperreflexia, dystonia, dysarthria, mild cognitive impairment, urinary urgency, and cerebellar atrophy. 

Molecular studies show increased MARS2 mRNA but decreased protein levels, along with impaired mitochondrial Complex I activity, elevated reactive oxygen species (ROS), and reduced cell proliferation. 

Disease severity varies, but about 50% of patients become wheelchair-dependent by their late 30s.

Combined Oxidative Phosphorylation Deficiency 25

Combined Oxidative Phosphorylation Deficiency 25 (COXPD25) results from compound heterozygous mutations such as Q184X and R142W. These impair mitochondrial Complex I and IV activity, reduce MARS2 protein levels, and can be partially rescued by reintroducing wild-type MARS2.

Research also links MARS2 to other multisystem mitochondrial phenotypes and developmental syndromes. Testing should be considered in children or adults with unexplained spastic ataxia, developmental delay, hearing loss, or biochemical signs of mitochondrial dysfunction. 

Common testing methods include CNV analysis, exome sequencing, and functional OXPHOS studies in fibroblasts.

Breast Cancer Metastasis

MARS2 is identified as a mitochondrial-related gene associated with breast cancer metastasis and was included in a machine learning–based predictive model that demonstrated strong performance in distinguishing metastatic from non-metastatic breast cancer cases.

MARS2 Genetic Testing: Test Procedure and Interpretation

Testing for MARS2 is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for MARS2 genetic testing are considered to be without mutations that can alter the activity of the MARS2 proteins.

What Do Altered Levels or Mutations in MARS2 Mean?

Loss-of-function mutations in MARS2 disrupt mitochondrial translation by impairing methionine charging of tRNA^Met. This causes reduced synthesis of mitochondrial-encoded proteins, particularly those in Complexes I and IV of the electron transport chain, and leads to OXPHOS deficiency. 

Resulting pathophysiological effects include:

• Mitochondrial dysfunction in neurons and muscle cells
• Accumulation of ROS
• Activation of the mitochondrial unfolded protein response (UPR^mt)
• Reduced cellular proliferation and energy production

Animal models such as Drosophila with disrupted MARS2 (Aats-met) exhibit neurodegeneration, flight muscle wasting, and shortened lifespan—phenotypes that are rescued by human MARS2 cDNA or antioxidant therapy (e.g., vitamin E). 

Patient-derived cells show decreased Complex I and IV activity, reduced MARS2 protein, and signs of oxidative stress. 

Functional rescue with overexpression of wild-type MARS2 confirms the gene’s essential role in mitochondrial health.

What Does the Absence of Specific Studied MARS2 Genetic Variations Mean?

The absence of previously described MARS2 mutations (e.g., those associated with SPAX3 or COXPD25) does not rule out mitochondrial disease. 

Many mitochondrial disorders involve different genes or novel variants not captured by standard panels. Therefore, isolated negative MARS2 findings should be interpreted in context. 

If clinical suspicion remains high, further testing (e.g., expanded exome/genome sequencing or functional assays) is warranted. Clinicians should also consider secondary mitochondrial dysfunction or polygenic contributions.

Summary for Clinical Practice

MARS2 encodes a mitochondrial enzyme critical for protein synthesis and OXPHOS function. Its loss leads to neurodegeneration, metabolic abnormalities, and impaired cell proliferation. Key clinical indications for testing include:

• Early-onset ataxia or spasticity
• White matter abnormalities on neuroimaging
• Multisystem mitochondrial features, including hearing loss, short stature, developmental delay, or elevated lactate

Pathogenic mechanisms involve mitochondrial translation failure, Complex I/IV deficiency, and ROS accumulation. Therapeutic angles include antioxidant strategies and, potentially, gene therapy with wild-type MARS2. 

Diagnostics should include CNV analysis, WES, and functional mitochondrial assays. 

In patient care, MARS2 should be considered when other causes of spastic ataxia or mitochondrial dysfunction are ruled out.

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