Mabul

Article about the MUTYH gene and its role in DNA repair and disease

MUTYH (mutY DNA glycosylase) is a human gene that encodes a DNA glycosylase enzyme involved in the base excision repair (BER) pathway. This enzyme plays a crucial role in maintaining genomic stability by correcting oxidative DNA damage, specifically by removing adenine bases that are misincorporated opposite 8-oxoguanine (8-oxoG), a common form of oxidative DNA damage.

Function

The MUTYH gene product is part of the DNA repair machinery that protects cells from mutations that can lead to cancer. The enzyme encoded by MUTYH is a DNA glycosylase that excises adenine bases that are incorrectly paired with 8-oxoG, a mutagenic lesion caused by reactive oxygen species. This action prevents G:C to T:A transversions, which are a type of point mutation.

Clinical significance

Mutations in the MUTYH gene are associated with a hereditary condition known as MUTYH-associated polyposis (MAP). MAP is an autosomal recessive disorder characterized by the development of multiple colorectal adenomas and an increased risk of colorectal cancer. Unlike familial adenomatous polyposis (FAP), which is caused by mutations in the APC gene, MAP typically presents with fewer polyps and has a later onset.

MUTYH-associated polyposis (MAP)

Individuals with biallelic mutations in the MUTYH gene have a significantly increased risk of developing colorectal cancer, often at a younger age than the general population. Genetic testing for MUTYH mutations can be an important tool in the management and surveillance of at-risk individuals.

Pathophysiology

The MUTYH protein functions in the base excision repair pathway, which is critical for repairing oxidative DNA damage. When MUTYH is mutated, the repair of 8-oxoG lesions is impaired, leading to an accumulation of mutations that can drive carcinogenesis. The most common mutations in the MUTYH gene associated with MAP are Y165C and G382D.

Research and future directions

Ongoing research is focused on understanding the full spectrum of mutations in the MUTYH gene and their phenotypic consequences. There is also interest in developing targeted therapies that can compensate for the loss of MUTYH function or enhance the repair of oxidative DNA damage.

Also see

• Base excision repair
• Colorectal cancer
• DNA repair
• Familial adenomatous polyposis
• Genetic testing