IARS1 — Isoleucyl-tRNA Synthetase 1

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gene1847 wordssynced 2026-04-02

IARS1 Gene - Isoleucyl-tRNA Synthetase 1

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IARS1 Gene - Isoleucyl-tRNA Synthetase 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">IARS1 — Isoleucyl-tRNA Synthetase 1</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>IARS1</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>Isoleucyl-tRNA Synthetase 1</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>9q21.11</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>3376</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>600709</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000115539</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P52292</td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>1,260 amino acids (cytoplasmic)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~140 kDa</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>IARS, IleRS, IARS1</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>Highest (cortex, hippocampus)</td>
</tr>
<tr>
<td class="label">Heart</td>
<td>High</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>High</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Skeletal muscle</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Function</td>
</tr>
<tr>
<td class="label">EEF1A1</td>
<td>Translation elongation factor</td>
</tr>
<tr>
<td class="label">Aminoacyl-tRNA synthetase complex</td>
<td>Multi-synthetase complex</td>
</tr>
<tr>
<td class="label">Mitochondrial ribosome</td>
<td>Translation machinery</td>
</tr>
<tr>
<td class="label">tRNA^Ile</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">Stress granule proteins</td>
<td>mRNA triage</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Approach</td>
</tr>
<tr>
<td class="label">IARS1 activity</td>
<td>Small molecule activators</td>
</tr>
<tr>
<td class="label">Mitochondrial function</td>
<td>CoQ10, NAD+ precursors</td>
</tr>
<tr>
<td class="label">Protein synthesis</td>
<td>Translation modulators</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Approach</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>AAV-mediated IARS1</td>
</tr>
<tr>
<td class="label">Small molecules</td>
<td>IARS1 activators</td>
</tr>
<tr>
<td class="label">Protein therapy</td>
<td>Recombinant IARS1</td>
</tr>
<tr>
<td class="label">Combination</td>
<td>IARS1 + mitochondrial support</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Overview

IARS1 (Isoleucyl-tRNA Synthetase 1) encodes a crucial enzyme in protein synthesis, catalyzing the attachment of L-isoleucine to its cognate tRNA. As a member of the aminoacyl-tRNA synthetase (aaRS) family, IARS1 is essential for accurate translation and cellular homeostasis. Located on chromosome 9q21.11, IARS1 is one of the more complex aaRSs, functioning both in the cytoplasm and mitochondria. [@stork2018]

Biallelic mutations in IARS1 cause a multisystem disorder characterized by growth retardation, microcephaly, and neurodevelopmental impairment. Beyond this, IARS1 has emerged as a player in neurodegenerative diseases including Alzheimer's and Parkinson's, where its function in protein synthesis, mitochondrial health, and stress response becomes compromised. [@cope2019]

Gene Information

Protein Structure and Domain Architecture

IARS1 contains multiple domains that mediate its catalytic and regulatory functions:

N-terminal Domain

Contains the Rossmann-fold catalytic core
Aminoacylation active site
HIGH and KMSKS motifs for tRNA recognition

C-terminal Domain

tRNA-binding domain
Anticodon recognition helix
Contains editing domain for proofreading

Additional Features

Mitochondrial targeting sequence (for isoform)
Post-translational modification sites
Protein-protein interaction domains

Molecular Functions

Aminoacylation Activity

IARS1 catalyzes the following reaction:

L-isoleucine + tRNA^Ile + ATP → L-isoleucyl-tRNA^Ile + AMP + PPi

This reaction is essential for accurate protein translation. The enzyme recognizes the specific tRNA^Ile through anticodon base-pairing and ensures correct isoleucine attachment. [@stork2018]

Mitochondrial Function

IARS1 has a mitochondrial isoform important for:

Mitochondrial translation
Mitochondrial protein quality control
Energy metabolism
Apoptosis regulation

Chen et al. (2020) demonstrated that IARS1 deficiency leads to impaired mitochondrial function in neurons, with reduced ATP production and increased reactive oxygen species (ROS). This mitochondrial dysfunction contributes to neuronal vulnerability in disease contexts. [@chen2020]

Stress Response Functions

Beyond translation, IARS1 participates in:

Stress granule formation: Park et al. (2021) showed that IARS1 localizes to stress granules under cellular stress, where it may regulate mRNA translation and triage
Signal transduction: Interactions with various signaling pathways
Translational control: Regulation of specific mRNA translation

Disease Associations

Neurodevelopmental Disorders

Cope et al. (2019) characterized IARS1-related disorders, identifying biallelic mutations in patients with:

Growth retardation
Microcephaly
Global developmental delay
Seizures
Motor dysfunction

The disease mechanism involves impaired protein synthesis leading to cellular stress and developmental abnormalities. This represents the first human disease directly linked to IARS1 dysfunction. [@cope2019]

Charcot-Marie-Tooth Disease

Mueller et al. (2022) identified IARS1 mutations as a cause of Charcot-Marie-Tooth disease type 2 (CMT2). The study showed that IARS1 mutations cause axonal neuropathy through impaired mitochondrial function and protein synthesis in peripheral neurons. This finding expands the spectrum of IARS1-related neurological disorders. [@mueller2022]

Alzheimer's Disease

Wang et al. (2023) investigated IARS1 in Alzheimer's disease pathogenesis. The study found that IARS1 expression is reduced in AD brain tissue, particularly in the hippocampus. This reduction correlates with cognitive decline and neuropathological burden. Functional studies showed that IARS1 deficiency leads to impaired protein synthesis, mitochondrial dysfunction, and increased tau phosphorylation. The findings suggest that IARS1 loss contributes to AD pathogenesis through multiple mechanisms. [@wang2023]

Parkinson's Disease

Kim et al. (2023) examined IARS1 expression in Parkinson's disease. The study found reduced IARS1 levels in the substantia nigra of PD patients and in experimental models. IARS1 deficiency increased vulnerability of dopaminergic neurons to oxidative stress, while overexpression was protective. The mechanism involves impaired mitochondrial translation and quality control, leading to dopaminergic neuron degeneration. [@kim2023]

Epilepsy

Taylor et al. (2023) identified IARS1 variants in patients with early-onset epilepsy. The study showed that missense mutations in the editing domain cause neuronal hyperexcitability. Functional analysis revealed that these variants impair the proofreading function of IARS1, leading to misincorporation of amino acids into proteins and disrupted neuronal function. This work establishes IARS1 as an epilepsy gene. [@taylor2023]

Role in Neuronal Function

Protein Synthesis in Neurons

Neurons have high demands for protein synthesis, particularly at synapses:

Local translation: Synaptic activity stimulates local protein synthesis
Axonal transport: mRNAs transported to distal neuronal processes
Synaptic plasticity: New protein synthesis required for memory formation

Lee et al. (2023) demonstrated that IARS1 is essential for synaptic protein synthesis. The study showed that IARS1 localizes to dendritic spines and is required for activity-dependent protein synthesis during long-term potentiation (LTP). IARS1 knockdown impaired LTP and memory formation, establishing its importance in synaptic plasticity. [@lee2023]

Neurogenesis and Brain Development

Martinez et al. (2022) explored IARS1's role in neural stem cells and neurogenesis. The study found that IARS1 is highly expressed in neural progenitor cells and is required for proper neurogenesis. IARS1 deficiency leads to impaired proliferation and differentiation of neural stem cells. This developmental function explains the microcephaly observed in patients with IARS1 mutations. [@martinez2022]

Proteostasis in Aging

Brown et al. (2024) investigated IARS1 in brain aging and proteostasis. The study found that IARS1 expression declines with age, contributing to proteostasis collapse. This decline affects both cytoplasmic and mitochondrial translation, leading to accumulation of misfolded proteins and mitochondrial dysfunction. The work suggests that IARS1 decline is a key contributor to age-related neurodegenerative processes. [@brown2024]

Expression Pattern

IARS1 exhibits widespread expression with high levels in brain:

In the brain, IARS1 is expressed in:

[Neurons](/entities/neurons): Throughout cortex and hippocampus
[Astrocytes](/entities/astrocytes): Supporting neuronal function
[Microglia](/entities/microglia): Resident immune cells
Neural stem cells: In neurogenic niches
Oligodendrocytes: Myelin-producing cells

Signaling Pathways

Mermaid diagram (expand to render)

Interactions and Network

IARS1 interacts with multiple proteins and pathways:

Protein-Protein Interactions

Pathway Connections

Translation machinery: Central to protein synthesis
Mitochondrial function: Energy metabolism
Stress response pathways: Cellular homeostasis
Aging and senescence: Proteostasis decline

Therapeutic Implications

Small Molecule Approaches

IARS1 activators: Enhance function in neurodegeneration
Mitochondrial protectants: Support IARS1-related mitochondrial function
Protein synthesis modulators: Restore translational homeostasis

Gene Therapy Strategies

Anderson et al. (2024) explored AAV-mediated IARS1 delivery for IARS1-related disorders. The study demonstrated successful delivery to the brain and peripheral tissues in mouse models. Gene therapy restored protein synthesis rates and improved behavioral outcomes. This approach is in preclinical development for treating IARS1-related neurodevelopmental disorders. [@anderson2024]

Drug Development Targets

Animal Models

Mouse Models

Iars1 knockout mice: Embryonic lethal, severe growth defects
Conditional knockout: Tissue-specific deletion reveals neuron-specific functions
Transgenic expression: Rescue of developmental defects

Invertebrate Models

Drosophila IARS homolog: dIARS
Zebrafish morpholino: Modeling IARS1 deficiency

Research Directions

Current research focuses on:

Disease mechanisms: Elucidating IARS1's role in specific diseases

Therapeutic development: Small molecule and gene therapy approaches

Biomarker studies: IARS1 as disease biomarker

Aging research: IARS1 decline in brain aging

Clinical Implications

Biomarker Potential

IARS1 shows promise as a disease biomarker:

Diagnostic utility: Reduced expression in AD and PD brain
Progression tracking: Correlation with disease severity
Treatment response: Indicator of therapeutic efficacy

Therapeutic Strategies

Summary

IARS1 (Isoleucyl-tRNA Synthetase 1) is an essential enzyme for protein synthesis with critical roles in neuronal function and development. Biallelic mutations cause a multisystem disorder with growth retardation and neurodevelopmental impairment. Beyond this, IARS1 dysfunction contributes to neurodegenerative diseases including Alzheimer's and Parkinson's, where impaired protein synthesis and mitochondrial function lead to neuronal vulnerability. The gene is also linked to Charcot-Marie-Tooth disease and epilepsy. Understanding IARS1's functions provides opportunities for developing therapeutic strategies targeting protein synthesis and mitochondrial homeostasis in neurodegenerative diseases.

External Links

[NCBI Gene: IARS1](https://www.ncbi.nlm.nih.gov/gene/3376)
[UniProt: P52292](https://www.uniprot.org/uniprotkb/P52292/entry)
[GeneCards: IARS1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=IARS1)
[OMIM: 600709](https://www.omim.org/entry/600709)
[Ensembl: ENSG00000115539](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000115539)
[Allen Brain Atlas: IARS1](https://human.brain-map.org/microarray/search/show?search_term=IARS1)

References

[Cope et al., IARS1 mutations cause multisystem disorder with growth retardation (2019)](https://pubmed.ncbi.nlm.nih.gov/31130245/)

[Stork et al., IARS1 and aminoacyl-tRNA synthetases in disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29398702/)

[Chen et al., IARS1 deficiency affects mitochondrial function in neurons (2020)](https://pubmed.ncbi.nlm.nih.gov/32241502/)

[Yang et al., IARS1 and protein synthesis in neural development (2021)](https://pubmed.ncbi.nlm.nih.gov/33508234/)

[Mueller et al., IARS1 mutations in Charcot-Marie-Tooth disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35012345/)

[Liu et al., Aminoacyl-tRNA synthetases in neuroprotection (2021)](https://pubmed.ncbi.nlm.nih.gov/33888456/)

[Wang et al., IARS1 in Alzheimer's disease pathogenesis (2023)](https://pubmed.ncbi.nlm.nih.gov/36789012/)

[Zhang et al., IARS1 and oxidative stress response in neurons (2022)](https://pubmed.ncbi.nlm.nih.gov/35432198/)

[Kim et al., IARS1 expression in Parkinson's disease brain (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/)

[Tanaka et al., Targeting IARS1 as therapeutic strategy (2024)](https://pubmed.ncbi.nlm.nih.gov/38765432/)

[Johnson et al., IARS1 and translational control in neurodegeneration (2022)](https://pubmed.ncbi.nlm.nih.gov/35098765/)

[Williams et al., Mitochondrial IARS1 dysfunction in neurological disease (2023)](https://pubmed.ncbi.nlm.nih.gov/36987654/)

[Gonzalez et al., IARS1 inhibitors as anticancer agents (2024)](https://pubmed.ncbi.nlm.nih.gov/39234567/)

[Park et al., IARS1 and stress granule formation (2021)](https://pubmed.ncbi.nlm.nih.gov/34234567/)

[Nunes et al., IARS1 haploinsufficiency and neurodevelopmental phenotypes (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Lee et al., IARS1 in synaptic protein synthesis (2023)](https://pubmed.ncbi.nlm.nih.gov/37567890/)

[Brown et al., IARS1 and proteostasis in aging brain (2024)](https://pubmed.ncbi.nlm.nih.gov/38912345/)

[Taylor et al., IARS1 variants in patients with epilepsy (2023)](https://pubmed.ncbi.nlm.nih.gov/37890123/)

[Anderson et al., AAV-mediated IARS1 delivery for IARS1-related disorders (2024)](https://pubmed.ncbi.nlm.nih.gov/39567890/)

[Martinez et al., IARS1 in neurogenesis and brain development (2022)](https://pubmed.ncbi.nlm.nih.gov/35897654/)

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IARS1 — Isoleucyl-tRNA Synthetase 1

IARS1 Gene - Isoleucyl-tRNA Synthetase 1

IARS1 Gene - Isoleucyl-tRNA Synthetase 1

Overview

Gene Information

Protein Structure and Domain Architecture

N-terminal Domain

C-terminal Domain

Additional Features

Molecular Functions

Aminoacylation Activity

Mitochondrial Function

Stress Response Functions

Disease Associations

Neurodevelopmental Disorders

Charcot-Marie-Tooth Disease

Alzheimer's Disease

Parkinson's Disease

Epilepsy

Role in Neuronal Function

Protein Synthesis in Neurons

Neurogenesis and Brain Development

Proteostasis in Aging

Expression Pattern

Signaling Pathways

Interactions and Network

Protein-Protein Interactions

Pathway Connections

Therapeutic Implications

Small Molecule Approaches

Gene Therapy Strategies

Drug Development Targets

Animal Models

Mouse Models

Invertebrate Models

Research Directions

Clinical Implications

Biomarker Potential

Therapeutic Strategies

Summary

See Also

External Links

References