On this page
RNASEH2C
ribonuclease H2 subunit C
RNASEH2C is located on the long (q) arm of chromosome 11, at band 11q13.1. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 11 in the library →Available at Jeen Health
Clinical tests that include this
Overview
RNASEH2C is located on chromosome 11 and encodes the smallest of three subunits that together form the ribonuclease H2 (RNase H2) enzyme complex. This complex plays a critical role in cellular housekeeping by degrading RNA-DNA hybrid structures that arise naturally during DNA copying. When RNASEH2C does not function properly, these hybrid molecules can accumulate and trigger harmful immune responses, particularly affecting the developing brain.
Pathogenic variants in RNASEH2C are associated with Aicardi-Goutières syndrome, a rare neurological condition characterised by early-onset brain inflammation, skin abnormalities, and immune system dysregulation. The gene appears on multiple NHS Genomic Medicine Service panels related to neurogenetics, reflecting its importance in inherited brain disorders and intracerebral calcification. Understanding RNASEH2C function helps explain how disruptions in basic DNA metabolism can lead to severe developmental and immunological consequences.
What the gene does
The protein encoded by RNASEH2C serves as the C subunit of the three-part RNase H2 complex, working alongside the A and B subunits to form a functional ribonuclease enzyme. This complex specifically recognises and cleaves RNA-DNA hybrid molecules - structures containing one RNA strand paired with one DNA strand - that form transiently during normal DNA replication in all cells.
Removing these hybrid structures is essential for maintaining genomic integrity, as persistent RNA-DNA hybrids can interfere with DNA replication machinery and potentially cause mutations. The RNase H2 complex also participates in DNA repair processes, helping to correct errors that occur when ribonucleotides (RNA building blocks) are mistakenly incorporated into DNA strands during replication.
Beyond its role in DNA metabolism, the RNase H2 complex contributes to immune regulation by degrading nucleic acid fragments that might otherwise be recognised as foreign material. When this clearance function fails, accumulated nucleic acids can activate innate immune pathways, leading to chronic inflammation. This connection between nucleic acid metabolism and immune activation explains why RNASEH2C dysfunction primarily manifests as an inflammatory brain disorder rather than a classical DNA repair syndrome.
Video: Genetics 101
Chromosome location
RNASEH2C is positioned at chromosomal band 11q13.1 on the long arm of chromosome 11. The gene spans a relatively compact genomic region and produces a transcript encoding a 164-amino acid protein. Its location in the q13.1 band places it amongst a cluster of genes with diverse functions, though no specific structural features of the genomic locus have been linked to disease susceptibility.
Protein structure
The RNASEH2C protein comprises 164 amino acids, making it the smallest subunit of the RNase H2 complex. The protein contains a disordered region spanning amino acids 91 to 112, which likely provides structural flexibility important for protein-protein interactions within the enzyme complex. Disordered regions in proteins often facilitate dynamic assembly with binding partners and may allow the RNase H2 complex to adapt its conformation when engaging different RNA-DNA hybrid substrates. The relatively small size of this subunit suggests it plays a structural or regulatory role rather than directly catalysing the enzymatic cleavage reaction, which is thought to be mediated primarily by the larger A subunit.
Key variants
Pathogenic variants in RNASEH2C are rare but clinically significant when they occur. Most disease-causing changes are loss-of-function variants that impair the stability or assembly of the RNase H2 complex, reducing the cell's capacity to remove RNA-DNA hybrids. The inheritance pattern and clinical severity can vary depending on the specific variants involved and whether both gene copies are affected.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Variants in RNASEH2C are primarily associated with Aicardi-Goutières syndrome, a severe neurological disorder characterised by early-onset encephalopathy, intracerebral calcification, and elevated interferon levels in cerebrospinal fluid. Affected individuals typically present in infancy with progressive brain dysfunction, skin lesions resembling chilblains, and developmental regression. The condition reflects aberrant immune activation caused by accumulated nucleic acid substrates that trigger interferon responses, leading to chronic neuroinflammation. Severity can range from profound disability with onset in the first weeks of life to milder presentations with later symptom onset, though all cases involve significant neurological impact.
No disease links recorded for this gene in our reference set.
UK clinical status
RNASEH2C appears on numerous NHS Genomic Medicine Service gene panels, reflecting its recognised role in inherited neurological and metabolic disorders. The gene holds green (diagnostic-grade) classification on panels including Childhood onset dystonia, chorea or related movement disorder (R57), Early onset or syndromic epilepsy (R59), Intellectual disability (R29), and Intracerebral calcification disorders. It is also listed on the Inherited white matter disorders panel, Adult onset leukodystrophy (R62), and Likely inborn error of metabolism (R98). This broad representation across neurogenetics panels indicates that RNASEH2C testing is considered clinically validated and relevant for diagnosing patients presenting with various neurological phenotypes, particularly those involving white matter abnormalities or intracerebral calcification.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the RNASEH2C protein do in cells?
The RNASEH2C protein forms part of the RNase H2 enzyme complex, which breaks down RNA-DNA hybrid molecules that form naturally during DNA copying. This activity is essential for maintaining genome stability and preventing inappropriate immune responses that can damage tissues, particularly in the brain.
How is RNASEH2C related to Aicardi-Goutières syndrome?
Pathogenic variants in RNASEH2C impair the RNase H2 complex's ability to remove RNA-DNA hybrids, leading to accumulation of nucleic acid fragments that trigger chronic immune activation. This results in the neuroinflammation and brain calcification characteristic of Aicardi-Goutières syndrome.
Is RNASEH2C testing available through the NHS?
Yes, RNASEH2C is included on multiple NHS Genomic Medicine Service panels for conditions involving neurological dysfunction, white matter abnormalities, and intracerebral calcification. Testing is typically arranged through specialist genetics services when clinical features suggest a relevant disorder.
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
- Chon H, Vassilev A, DePamphilis ML. Contributions of the two accessory subunits, RNASEH2B and RNASEH2C, to the activity and properties of the human RNase H2 complex. Nucleic acids research. 2009. PMID: 19015152
- 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