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MUTYH
mutY DNA glycosylase
The MUTYH gene provides instructions for an enzyme crucial in DNA repair, particularly in correcting errors that can lead to MUTYH-associated polyposis, an inherited condition increasing colorectal cancer risk. MUTYH, or mutY DNA glycosylase, plays a vital role in maintaining the integrity of our genetic material by repairing specific types of DNA damage.
MUTYH is located on the short (p) arm of chromosome 1, at band 1p34.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The MUTYH gene, also known as mutY DNA glycosylase, is central to the body's DNA repair machinery. It encodes an enzyme that helps to correct errors that can occur during DNA replication, particularly those arising from oxidative damage. These repair mechanisms are essential for preventing the accumulation of genetic alterations that could lead to disease.
Pathogenic variants within the MUTYH gene are primarily associated with MUTYH-associated polyposis (MAP), an inherited condition that significantly increases an individual's lifetime risk of developing colorectal cancer. MAP is inherited in an autosomal recessive manner, meaning that an individual typically needs to inherit pathogenic variants in both copies of the MUTYH gene to develop the condition.
What the gene does
The MUTYH gene is responsible for producing adenine DNA glycosylase, an enzyme integral to the base excision repair (BER) pathway. This pathway is a fundamental mechanism for repairing damaged DNA, thereby preserving genomic stability. Specifically, the adenine DNA glycosylase enzyme targets a common type of DNA damage caused by oxidation of guanine bases.
When reactive oxygen species damage DNA, they can chemically modify guanine bases. During subsequent DNA replication, these oxidised guanine residues will aberrantly pair with adenine rather than their normal cytosine partner. The MUTYH enzyme acts to remove the incorrectly inserted adenine from these mispaired bases. Following the removal of adenine, other enzymes in the BER pathway then complete the repair by excising the damaged guanine and synthesising the correct base pair. This precise function of MUTYH is critical for preventing the accumulation of mutations that could contribute to carcinogenesis. A dysfunctional MUTYH enzyme, due to pathogenic variants, leads to a failure in correcting these oxidative DNA damages, subsequently increasing mutation rates and cancer risk.
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Chromosome location
The MUTYH gene is situated on the short arm of chromosome 1, specifically at position 1p34.1. This genomic location specifies the exact address of the gene within the human genome. The MUTYH gene spans a considerable region of DNA and contains multiple exons, which are the coding segments of the gene that are ultimately translated into protein. Its precise mapping to 1p34.1 helps in genetic diagnostics and research into conditions associated with MUTYH.
Protein structure
The MUTYH protein is composed of 546 amino acids and exhibits a modular structure with distinct functional regions. A disordered region is located at amino acids 19-51. This region typically lacks a fixed three-dimensional structure but can play important roles in protein-protein interactions and regulation. The core enzymatic activity is associated with the Nudix hydrolase domain, spanning amino acids 364-495. Within this domain, a critical Nudix box motif is found between amino acids 404-426 and is characteristic of the Nudix hydrolase superfamily, serving as a conserved sequence element essential for catalytic function.
Key variants
Variants within the MUTYH gene can range from single nucleotide changes to larger deletions or duplications. Not all genetic variations are pathogenic; many are benign polymorphisms that do not affect gene function. Pathogenic variants, however, can impair the MUTYH protein's ability to repair DNA, leading to an increased risk of specific health conditions. These variants are typically identified through genetic testing, which can inform risk assessment and management strategies.
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.1016_1017del | p.Pro339fs | Pathogenic/Likely pathogenic | ★★☆☆ | Familial adenomatous polyposis 2 |
c.1017del | p.Arg340fs | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1017dup | p.Arg340fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.102_103insGT | p.Ser35fs | Pathogenic | ★★☆☆ | Familial adenomatous polyposis 2 |
c.1051C>T | p.Gln351Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1057_1064del | p.Gly353fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1063del | p.Ala357fs | Pathogenic/Likely pathogenic | ★★☆☆ | not specified |
c.1079T>C | p.Leu360Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Familial adenomatous polyposis 2 |
c.1087C>T | p.Gln363Ter | Pathogenic | ★★☆☆ | Carcinoma of colon |
c.1102+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
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
Pathogenic variants in the MUTYH gene are primarily associated with MUTYH-associated polyposis (MAP). MAP is an inherited disorder characterised by the development of multiple adenomatous polyps throughout the colon and rectum. Individuals with MAP have a greatly increased lifetime risk of colorectal cancer.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic MUTYH 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 MUTYH gene is recognised on several NHS Genomic Medicine Service clinical panels, reflecting its clinical significance. It is included in panels for 'Additional findings health related' for both adult and adult-specific CNV analysis, indicating its role in conditions detected as secondary findings. MUTYH is also part of 'Adult solid tumours cancer susceptibility' and 'GI tract tumours' panels, as well as the 'Inherited polyposis and early onset colorectal cancer - germline testing' panel (R211). Its inclusion highlights its importance in assessing inherited cancer risk, particularly for gastrointestinal cancers.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research suggests that maintaining a healthy lifestyle may contribute to overall well-being, though there is no conclusive evidence that specific lifestyle changes can prevent the development of conditions associated with MUTYH variants. A balanced diet rich in fruits, vegetables, and whole grains, along with regular physical activity, is generally recommended for the general population. Avoiding smoking and excessive alcohol consumption are also widely accepted as beneficial for reducing cancer risk in the general population.
Supplement considerations
There is currently no conclusive scientific evidence to suggest that specific dietary supplements can prevent or treat conditions associated with MUTYH variants. Individuals considering supplements should always consult with a healthcare professional, as some supplements can interact with medications or have unintended side effects. The focus for managing genetic conditions should remain on established medical care and surveillance strategies advised by healthcare providers.
Frequently asked questions
What is the primary function of the MUTYH gene?
The MUTYH gene encodes an enzyme called adenine DNA glycosylase, which is critical for DNA repair. It specifically removes incorrectly paired adenine bases from DNA that has been damaged by oxidation, thereby preventing mutations.
What is MUTYH-associated polyposis (MAP)?
MAP is an inherited condition caused by pathogenic variants in both copies of the MUTYH gene. It leads to the development of multiple polyps in the colon and rectum, significantly increasing the risk of colorectal cancer.
How is MUTYH-associated polyposis inherited?
MAP is inherited in an autosomal recessive manner. This means an individual must inherit a pathogenic variant from each parent to develop the condition. Individuals with one pathogenic variant are typically carriers.
Is the MUTYH gene included in UK genetic testing panels?
Yes, the MUTYH gene is included in several NHS Genomic Medicine Service clinical panels in the UK, particularly those related to hereditary cancer susceptibility and inherited polyposis. This reflects its importance in assessing genetic risk.
References
- Farrington SM, Tenesa A, Barnetson R. Germline susceptibility to colorectal cancer due to base-excision repair gene defects. American journal of human genetics. 2005. PMID: 15931596