RNASEH2A: Ribonuclease H2 Subunit A
A key component of the RNase H2 complex involved in DNA replication and repair, associated with Aicardi-Goutières syndrome and cancer.
Gene Information Card
| Symbol | RNASEH2A |
|---|---|
| Full Name | ribonuclease H2 subunit A |
| Gene Type | protein-coding |
| Chromosomal Location | 19p13.13 |
| NCBI Gene ID | 10535 ncbi.nlm.nih.gov/gene/10535 |
| Ensembl ID | ENSG00000104889 |
| UniProt ID | O75792 |
| OMIM ID | 606034 |
| HGNC ID | 18518 |
| Aliases | RNASEH2A, AGS4, JUNB, RNASEHI, RNHIA |
Description
RNASEH2A encodes the catalytic subunit A of the RNase H2 complex, which cleaves ribonucleotides misincorporated into DNA during replication. This enzyme is essential for ribonucleotide excision repair (RER) and genome stability. Mutations in RNASEH2A cause Aicardi-Goutières syndrome type 4 (AGS4), a severe autoimmune disorder. The gene is also implicated in certain cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Aicardi-Goutières syndrome 4 (AGS4) | Loss-of-function mutations impair RNase H2 activity, leading to accumulation of ribonucleotides in DNA, triggering chronic interferon signaling and neuroinflammation. | OMIM #610181; ClinVar |
| Systemic lupus erythematosus (SLE) | RNASEH2A variants may contribute to autoimmune pathogenesis via defective nucleic acid processing. | ClinVar; PMID: 25741868 |
| Breast cancer | Somatic mutations and altered expression of RNASEH2A are associated with genomic instability and tumor progression. | COSMIC; PMID: 26689913 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 45.2 | High |
| Bone marrow | 32.1 | High |
| Lymph node | 28.7 | High |
| Brain | 12.3 | Medium |
| Liver | 8.9 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 35.6 | Embryonic kidney; high expression |
| HeLa | 29.4 | Cervical carcinoma; moderate-high |
| K562 | 22.1 | Leukemia; moderate |
| MCF7 | 18.3 | Breast cancer; moderate |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.205C>T (p.Arg69Trp) | Missense | Rare (found in AGS4 families) | Loss of RNase H2 catalytic activity; causes AGS4 |
| c.494G>A (p.Arg165His) | Missense | Rare | Impaired complex assembly; associated with AGS4 |
| c.1A>G (p.Met1Val) | Start loss | Rare | Complete loss of protein; severe AGS4 phenotype |
Mutation functional classification
Loss of Function (LOF)
Most RNASEH2A mutations are loss-of-function, reducing or abolishing RNase H2 activity, leading to ribonucleotide accumulation and genomic instability.
Gain of Function (GOF)
No gain-of-function mutations reported.
Dominant Negative (DN)
Some missense mutations may exert dominant-negative effects by disrupting complex assembly, though evidence is limited.
View complete mutation data：
Gene Ontology (GO)
| • RNA-DNA hybrid ribonuclease activity (GO:0004523) | • cytoplasm (GO:0005737) |
| • nucleus (GO:0005634) | • DNA repair (GO:0006281) |
| • nucleotide-excision repair (GO:0006297) | • DNA replication (GO:0043137) |
Pathways
• Ribonucleotide excision repair (RER)
• DNA replication
• Interferon signaling (via cGAS-STING)
Protein Summary
RNASEH2A is the catalytic subunit of the heterotrimeric RNase H2 complex. It specifically cleaves ribonucleotides embedded in DNA, a critical function for maintaining genome integrity. The protein contains a conserved RNase H-like domain and is ubiquitously expressed. Defects in RNASEH2A lead to Aicardi-Goutières syndrome, a severe neuroinflammatory disorder, and are linked to cancer susceptibility.
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