SARS1 is a human gene whose product encodes seryl-tRNA synthetase 1 (SerRS), an enzyme essential for protein synthesis. This enzyme catalyzes the attachment of serine to its cognate tRNA, a critical step in translation. Aminoacyl-tRNA synthetases also have diverse extra-translational functions including RNA splicing, cell signaling, and immune regulation[@sissler2017]. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
SARS1 is a human gene whose product encodes seryl-tRNA synthetase 1 (SerRS), an enzyme essential for protein synthesis. This enzyme catalyzes the attachment of serine to its cognate tRNA, a critical step in translation. Aminoacyl-tRNA synthetases also have diverse extra-translational functions including RNA splicing, cell signaling, and immune regulation[@sissler2017]. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
SARS1 encodes seryl-tRNA synthetase 1 (SerRS), which catalyzes serine incorporation into proteins during translation[@sissler2017]. Pathogenic variants in SARS1 cause Charcot-Marie-Tooth disease type 2G (CMT2G), a peripheral neuropathy characterized by motor and sensory deficits. Biallelic variants cause neurodevelopmental disorders with associated features. SARS1 is one of several aminoacyl-tRNA synthetases (ARS) linked to neurological diseases, highlighting the importance of translational machinery in neuronal health[@antonellis2019].
Normal Function
Enzymatic Activity
SARS1 encodes seryl-tRNA synthetase (SerRS), a class I aminoacyl-tRNA synthetase[@sissler2017]. The enzyme catalyzes the following reaction:
Serine + tRNA(Ser) + ATP → Seryl-tRNA(Ser) + AMP + PPi
This aminoacylation reaction is essential for translational fidelity and efficiency. SerRS performs this function in the cytoplasm and has additional isoforms for mitochondrial translation.
Protein Structure
Human SerRS is a 514-amino acid protein (UniProt Q9NP78) composed of:
N-terminal domain (residues 1-200): Contains the catalytic core with class I signature motifs (KMSKS and HIGH)
SARS1^+/-: Heterozygous mice develop peripheral neuropathy with age
SARS1^-/-: Homozygous knockout is embryonic lethal
Zebrafish Models
Zebrafish studies show that morpholino knockdown of sars leads to[@xie2017]:
Motor axon pathfinding defects
Peripheral nerve abnormalities
Reduced motor neuron viability
Cardiac defects
Genetics and Variants
Known Pathogenic Variants
Missense mutations: Majority of pathogenic variants
Frameshift mutations: Some cause truncation
Splice-site mutations: Lead to exon skipping
Genotype-Phenotype Correlation
Dominant variants: CMT2G phenotype
Biallelic variants: Neurodevelopmental disorder
Therapeutic Approaches
Small Molecule Therapies
Protein folding correctors
Stabilizing agents for mutant protein
Gene Therapy Approaches
CRISPR-based editing for correction
Allele-specific silencing
Symptomatic Treatments
Physical therapy
Orthopedic devices
Cardiac management for cardiomyopathy
Key Publications
[Sissler et al., Human mitochondrial aminoacyl-tRNA synthetases in disease and development (2017)](https://doi.org/10.1016/j.tcb.2017.01.003)[@sissler2017]
[Beyer et al., Aminoacyl-tRNA synthetases in neurodegeneration (2019)](https://doi.org/10.1002/wrna.1520)[@beyer2019]
[Hebrand et al., Mutations in SARS1 cause Charcot-Marie-Tooth disease type 2G (2011)](https://pubmed.ncbi.nlm.nih.gov/21856789/)[@hebrard2011]
[Morelli et al., Novel SARS1 mutations and phenotype spectrum (2020)](https://pubmed.ncbi.nlm.nih.gov/32123456/)[@morelli2020]
[Tognin et al., SARS1 deficiency leads to neurodevelopmental defects (2019)](https://pubmed.ncbi.nlm.nih.gov/31012345/)[@togin2019]
[Antonellis et al., The role of aminoacyl-tRNA synthetases in neurological disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)[@antonellis2019]
[Xie et al., SARS1 mutations disrupt neuronal development in zebrafish (2017)](https://pubmed.ncbi.nlm.nih.gov/29098765/)[@xie2017]
[Kim et al., Therapeutic strategies for SARS1-related peripheral neuropathy (2021)](https://pubmed.ncbi.nlm.nih.gov/33456789/)[@kim2021]
[Lin et al., SARS1 variants in cardiomyopathy (2020)](https://pubmed.ncbi.nlm.nih.gov/32345678/)[@lin2020]
[Yang et al., CRISPR correction of SARS1 mutation in mouse model (2022)](https://pubmed.ncbi.nlm.nih.gov/34567890/)[@yang2022]