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IARS1 — Isoleucyl-tRNA Synthetase 1
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>
<t
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
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:
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.
See Also
- [Aminoacyl-tRNA Synthetases](/mechanisms/protein-synthesis)
- [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction-pathway)
- [Protein Synthesis](/mechanisms/translation)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Charcot-Marie-Tooth Disease](/diseases/charcot-marie-tooth-disease)
- [Neurodevelopmental Disorders](/diseases/neurodevelopmental-disorders)
- [Synaptic Plasticity](/mechanisms/synaptic-plasticity)
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
▸Metadataorigin_type: v1_polymorphic_backfill
| slug | genes-iars1 |
| kg_node_id | IARS1 |
| entity_type | gene |
| origin_type | v1_polymorphic_backfill |
| source_table | wiki_pages |
| wiki_page_id | wp-fbf93f73cae8 |
| __merged_from | {'merged_at': '2026-05-13', 'unprefixed_id': 'genes-iars1'} |
| _schema_version | 1 |
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