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NTHL1
nth like DNA glycosylase 1
The NTHL1 gene provides instructions for making a protein involved in base excision repair, a key pathway for correcting DNA damage and maintaining genomic stability within cells. The NTHL1 gene is essential for cellular defence against DNA damage, ensuring the integrity of the genome.
NTHL1 is located on the short (p) arm of chromosome 16, at band 16p13.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The NTHL1 gene, standing for nth like DNA glycosylase 1, is a human gene that plays a fundamental biological role in protecting our cells from errors in their genetic code. It encodes a DNA glycosylase enzyme, which is a critical component of the base excision repair (BER) pathway. This pathway is one of the primary mechanisms cells use to identify and correct damaged DNA bases, preventing mutations that could lead to disease.
Inherited changes in the NTHL1 gene can impair this vital repair process, increasing an individual's susceptibility to certain health conditions, particularly hereditary cancers. Understanding the NTHL1 gene's function and its associated variants is important for identifying individuals at higher risk and for advancing precision medicine approaches.
What the gene does
The protein produced from the NTHL1 gene functions as an N-glycosylase and an AP-lyase within the base excision repair (BER) pathway. Its primary role involves recognising and removing damaged or modified nitrogenous bases from DNA, which can arise from oxidative stress or alkylation. Once a damaged base is identified, NTHL1 excises it, creating an apurinic/apyrimidinic (AP) site.
Following base removal, the NTHL1 protein further processes the AP site through its AP-lyase activity. This involves cleaving the DNA backbone at the AP site, creating a break that can then be processed by other enzymes in the BER pathway. This two-step activity - base removal and DNA strand cleavage - makes NTHL1 highly efficient in initiating the repair process for oxidatively damaged DNA bases such as thymine glycol, amongst others. By diligently excising damaged bases and initiating their repair, NTHL1 prevents the accumulation of DNA lesions that could otherwise lead to genomic instability, mutations, and potentially cancer development.
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Chromosome location
The NTHL1 gene is located on chromosome 16, specifically at position 16p13.3. This means it is found on the short arm (p) of chromosome 16, within band 13.3. The human genome contains approximately 20,000 to 25,000 genes, and NTHL1 is one of many genes precisely mapped to specific chromosomal locations, which helps in genetic studies and diagnostics.
Protein structure
The NTHL1 protein consists of 304 amino acids and has a precise structural organisation that facilitates its DNA repair functions. A significant portion of its N-terminal region, spanning amino acids 1-72, is characterised as a Disordered region. This flexibility may be important for protein-protein interactions or conformational changes during DNA binding and repair. Crucially, between amino acids 28 and 52, the protein contains a Bipartite nuclear localization signal motif, which is essential for directing the NTHL1 protein into the cell nucleus where it performs its DNA repair functions. Furthermore, a HhH (helix-hairpin-helix) domain is present from amino acids 191 to 215. This domain is commonly found in DNA glycosylases and is vital for recognising and binding to damaged DNA bases, enabling the protein to initiate the base excision repair pathway.
Key variants
Genetic variants in the NTHL1 gene can significantly impact its function. These variants can range from single base changes to larger deletions or insertions, and their effect depends on where they occur within the gene and how they alter the resulting protein. Some variants may lead to a non-functional protein, while others might only reduce its efficiency in DNA repair. Pathogenic variants, which are known to cause disease, typically impair the NTHL1 protein's ability to identify and remove damaged DNA bases, or to cleave the DNA backbone, thereby compromising the cell's DNA repair capacity. The presence of such variants can predispose individuals to certain hereditary conditions, particularly those involving an increased risk of cancer.
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.115+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.116-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.138del | p.Pro46_Val47insTer | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.160_161del | p.Gln54fs | Pathogenic | ★★☆☆ | not provided |
c.160C>T | p.Gln54Ter | Pathogenic | ★★☆☆ | not provided |
c.164_165del | p.Arg55fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.167_168del | p.Leu56fs | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.199A>T | p.Lys67Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial adenomatous polyposis 3 |
c.203del | p.Gly68fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.211dup | p.Ala71fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
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
Inherited pathogenic variants in the NTHL1 gene are associated with an increased risk of developing certain types of cancer. Individuals with biallelic (two copies) pathogenic variants in NTHL1 are known to have NTHL1-associated polyposis, a condition characterised by the development of multiple adenomatous polyps in the colon and an elevated lifetime risk of colorectal cancer, as well as other cancers such as duodenal, breast, and brain tumours. This genetic predisposition underscores the NTHL1 gene's critical role in maintaining genomic stability and preventing unchecked cell growth.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic NTHL1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
In the UK, the NTHL1 gene is recognised within clinical genomics pathways, highlighting its importance in inherited disease susceptibility. It is currently listed on several NHS Genomic Medicine Service national test directories. NTHL1 is included in the Adult solid tumours cancer susceptibility panel, the Adult solid tumours for rare disease panel, the Colorectal cancer pertinent cancer susceptibility panel, and the GI tract tumours panel, all with a 'green' status, indicating that there is strong evidence for its clinical utility in these contexts. Furthermore, it is part of the Inherited polyposis and early onset colorectal cancer - germline testing panel (R211), also marked 'green', confirming its relevance in identifying genetic predisposition to these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research suggests that certain lifestyle factors may influence overall cancer risk in the general population, although evidence specifically linking these to NTHL1-related conditions is limited. Generally, maintaining a healthy body weight, engaging in regular physical activity, and consuming a diet rich in fruits, vegetables, and whole grains may contribute to overall health and potentially lower cancer risk. Limiting processed foods, red meat, and alcohol consumption is also widely recommended. Avoiding smoking is a crucial step in reducing cancer risk, as tobacco smoke contains numerous carcinogens that can damage DNA. These general health recommendations are beneficial for everyone, but they are not a substitute for medical advice or surveillance for individuals with a known genetic predisposition.
Supplement considerations
There is currently no conclusive evidence that specific dietary supplements can prevent or treat conditions associated with NTHL1 gene variants. While some supplements contain antioxidants that are purported to reduce DNA damage, their efficacy in mitigating the effects of compromised DNA repair pathways like those involving NTHL1 has not been established. Individuals considering any supplements should discuss this with their healthcare provider, especially if they have a known genetic predisposition, to ensure safety and appropriateness.
Frequently asked questions
What is the primary function of the NTHL1 gene?
The NTHL1 gene provides instructions for creating a protein vital to the base excision repair (BER) pathway. This protein recognises and removes damaged DNA bases, initiating the repair process to maintain genomic integrity.
How can NTHL1 gene variants affect health?
Pathogenic variants in the NTHL1 gene can impair its DNA repair function, leading to an accumulation of DNA damage. This increased genetic instability is associated with a higher risk of developing certain hereditary cancers, including colorectal cancer.
What is NTHL1-associated polyposis?
NTHL1-associated polyposis is a genetic condition caused by having two pathogenic variants in the NTHL1 gene. It is characterised by the development of numerous polyps in the colon and an increased risk of various cancers.
Is regular screening recommended for individuals with NTHL1 variants?
Individuals with identified pathogenic NTHL1 variants, especially those with biallelic variants, are typically recommended for increased surveillance and screening. This often includes regular colonoscopies and monitoring for other associated cancers to facilitate early detection and intervention.
Is NTHL1 testing available in the UK?
Yes, NTHL1 gene testing is available in the UK through the NHS Genomic Medicine Service. It is included on several national test directories related to hereditary cancer susceptibility and inherited polyposis conditions.