HARS2: Histidyl-tRNA Synthetase 2, Mitochondrial
A nuclear-encoded mitochondrial aminoacyl-tRNA synthetase implicated in Perrault syndrome and ovarian dysfunction.
Gene Information Card
| Symbol | HARS2 |
|---|---|
| Full Name | Histidyl-tRNA Synthetase 2, Mitochondrial |
| Gene Type | Protein coding |
| Chromosomal Location | 5q31.3 |
| NCBI Gene ID | 23438 ncbi.nlm.nih.gov/gene/23438 |
| Ensembl ID | ENSG00000112855 |
| UniProt ID | P49590 |
| OMIM ID | 600783 |
| HGNC ID | 4817 |
| Aliases | HARS, HARSL, HARSR, HisRS, MTOPS |
Description
HARS2 encodes the mitochondrial histidyl-tRNA synthetase, which catalyzes the attachment of histidine to its cognate tRNA in mitochondria. This enzyme is essential for mitochondrial protein synthesis. Mutations in HARS2 cause Perrault syndrome (sensorineural hearing loss and ovarian dysgenesis) and are associated with primary ovarian insufficiency.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Perrault syndrome 2 | Biallelic loss-of-function mutations impair mitochondrial translation, leading to sensorineural hearing loss and ovarian dysgenesis. | ClinVar, OMIM |
| Primary ovarian insufficiency 8 | Heterozygous or compound heterozygous variants disrupt mitochondrial protein synthesis in granulosa cells, causing premature ovarian failure. | ClinVar, OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Ovary | 12.5 | Medium |
| Fallopian tube | 10.3 | Medium |
| Testis | 9.8 | Medium |
| Heart | 8.2 | Medium |
| Skeletal muscle | 7.1 | Low |
| Brain | 6.5 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 14.2 | High expression |
| K562 | 11.0 | Medium expression |
| HepG2 | 9.5 | Medium expression |
| A549 | 8.1 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.428G>A (p.Arg143Gln) | Missense | Rare | Reduced catalytic activity; associated with Perrault syndrome |
| c.1379G>A (p.Arg460His) | Missense | Rare | Impaired tRNA binding; linked to primary ovarian insufficiency |
| c.1A>G (p.Met1Val) | Start loss | Very rare | Loss of translation initiation; likely pathogenic |
Mutation functional classification
Loss of Function (LOF)
Most reported HARS2 mutations reduce or abolish enzymatic activity, impairing mitochondrial translation.
Gain of Function (GOF)
No gain-of-function mutations reported.
Dominant Negative (DN)
Not described; disease inheritance is autosomal recessive.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Mitochondrial tRNA aminoacylation
• Aminoacyl-tRNA biosynthesis (mitochondrial)
Protein Summary
HARS2 is a 509-amino-acid mitochondrial histidyl-tRNA synthetase. It belongs to the class II aminoacyl-tRNA synthetase family and is essential for charging mitochondrial tRNA(His) with histidine. The protein is nuclear-encoded and imported into mitochondria. Defects in HARS2 disrupt mitochondrial protein synthesis, leading to tissue-specific energy deficits, particularly in the cochlea and ovaries.
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