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RNASEH2A
ribonuclease H2 subunit A
The RNASEH2A gene provides instructions for a key component of the RNase H2 complex, an enzyme crucial for processing RNA-DNA hybrids and maintaining genomic stability. RNASEH2A encodes a subunit of the RNase H2 complex, an enzyme responsible for breaking down RNA-DNA hybrid molecules.
RNASEH2A is located on the short (p) arm of chromosome 19, at band 19p13.13. Arm ratio per GRCh38 - banding schematic.
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Overview
The RNASEH2A gene provides instructions for one part of the ribonuclease H2 (RNase H2) protein complex. This complex functions as an enzyme that degrades molecules composed of both RNA and DNA, known as RNA-DNA hybrids. Such hybrid structures naturally form within cells, particularly during DNA replication.
Beyond its role in processing RNA-DNA hybrids, the RNase H2 complex, and thus the protein product of the RNASEH2A gene, is also involved in essential cellular functions like DNA replication and the correction of DNA errors. Impaired activity of this complex can have significant health consequences, including its association with inherited conditions.
What the gene does
The protein produced from the RNASEH2A gene is a vital component of the RNase H2 complex. This complex demonstrates ribonuclease activity, meaning it acts as an enzyme to break down RNA-containing molecules. Its primary role involves the degradation of RNA-DNA hybrids, transient structures that emerge during DNA replication in all cells.
The RNase H2 complex's function is crucial not only for eliminating these hybrid molecules but also for efficient DNA replication and the accurate repair of DNA damage. Furthermore, it is believed to contribute to immune system regulation by removing specific DNA fragments, thereby helping to prevent undesired immune responses.
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Chromosome location
The RNASEH2A gene is found on chromosome 19. Its precise location is 19p13.13, which refers to position 13.13 on the short arm (p) of this chromosome. This region contains the genetic blueprint for producing the ribonuclease H2 subunit A protein.
Protein structure
The RNASEH2A protein consists of 299 amino acids. A notable structural feature of this protein is an RNase H type-2 domain, which spans approximately from amino acid 28 to 250. This domain is essential for the protein's ribonuclease activity, enabling it to interact with and break down RNA-DNA hybrid molecules.
Key variants
Genetic variations, or variants, within the RNASEH2A gene can alter the protein's structure or how it functions. Such alterations may reduce the effectiveness of the RNase H2 complex, hindering its ability to process RNA-DNA hybrids or participate in DNA repair. The effects of specific variants can range in severity, depending on their impact on protein function.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.206dup | p.Thr70fs | Pathogenic/Likely pathogenic | ★★☆☆ | RNASEH2A-related disorder |
c.447C>A | p.Tyr149Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Aicardi-Goutieres syndrome 4 |
c.543_544del | p.Ala182fs | Pathogenic/Likely pathogenic | ★★☆☆ | Aicardi-Goutieres syndrome 4 |
c.556C>T | p.Arg186Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Aicardi Goutieres syndrome |
c.557G>A | p.Arg186Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Aicardi Goutieres syndrome |
c.589del | p.Glu197fs | Pathogenic | ★★☆☆ | RNASEH2A-related disorder |
c.657G>A | p.Trp219Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Aicardi-Goutieres syndrome 4 |
c.205_208del | p.Lys69fs | Pathogenic | ★☆☆☆ | Aicardi-Goutieres syndrome 4 |
c.238_241del | p.Phe80fs | Pathogenic | ★☆☆☆ | Aicardi-Goutieres syndrome 4 |
c.403_406dup | p.Thr136fs | Pathogenic | ★☆☆☆ | Aicardi-Goutieres syndrome 4 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the RNASEH2A gene are linked to several inherited disorders, most notably Aicardi-Goutières syndrome. This condition is an autosomal recessive disorder characterised by severe brain dysfunction (encephalopathy), skin lesions, and other health problems. The specific clinical presentation and severity can vary among affected individuals.
UK clinical status
The RNASEH2A gene is included in several expert-curated panels within the UK National Health Service (NHS) Genomic Medicine Service's PanelApp. It is listed as 'green' for conditions such as COVID-19 research, DDG2P, Early onset or syndromic epilepsy, Foetal anomalies (R21), Inherited white matter disorders, Intellectual disability, Intracerebral calcification disorders, Leukodystrophy, adult onset (R62), Likely inborn error of metabolism (R98), Primary immunodeficiency or monogenic inflammatory bowel disease (R15), and White matter disorders and cerebral calcification - childhood onset, indicating strong evidence for its involvement in these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the RNASEH2A gene?
The RNASEH2A gene provides instructions for a subunit of the RNase H2 complex, an enzyme that primarily breaks down RNA-DNA hybrid molecules. This process is crucial for correct DNA replication and repair.
What health conditions are associated with RNASEH2A gene variants?
Variants in the RNASEH2A gene are linked to Aicardi-Goutières syndrome, a severe neurological disorder. This condition is characterised by brain dysfunction and other health problems.
How does the RNASEH2A protein contribute to DNA repair?
The RNASEH2A protein, as part of the RNase H2 complex, helps remove RNA-DNA hybrids that can impede DNA replication and repair mechanisms. This ensures the integrity and stability of the genome.
References
- Feng S, Cao Z. Is the role of human RNase H2 restricted to its enzyme activity? Progress in biophysics and molecular biology. 2016. PMID: 26603688
- Livingston JH, Crow YJ. Neurologic Phenotypes Associated with Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutières Syndrome and Beyond. Neuropediatrics. 2016. PMID: 27643693
- Crow YJ, Chase DS, Lowenstein Schmidt J. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. American journal of medical genetics. Part A. 2015. PMID: 25604658
- Cuadrado E, Michailidou I, van Bodegraven EJ. Phenotypic variation in Aicardi-Goutières syndrome explained by cell-specific IFN-stimulated gene response and cytokine release. Journal of immunology (Baltimore, Md. : 1950). 2015. PMID: 25769924
- Rice GI, Forte GM, Szynkiewicz M. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. The Lancet. Neurology. 2013. PMID: 24183309
- Perrino FW, Harvey S, Shaban NM. RNaseH2 mutants that cause Aicardi-Goutieres syndrome are active nucleases. Journal of molecular medicine (Berlin, Germany). 2009. PMID: 19034401
- Rice G, Patrick T, Parmar R. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. American journal of human genetics. 2007. PMID: 17846997
- Adam MP, Bick S, Mirzaa GM. Aicardi-Goutières Syndrome. 1993. PMID: 20301648