Investigations of Genetic Variation in Families affected by MUTYH-associated Polyposis
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PROVIDER: PRJNA1076658 | ENA |
REPOSITORIES: ENA
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Project description:Investigations of Genetic Variation in Families affected by MUTYH-associated Polyposis
| PRJNA1076659 | ENA
Project description:Progression of duodenal polyposis into cancer is an important cause of morbidity and mortality in the inherited tumour syndromes Familial Adenomatous Polyposis (FAP) and MUTYH-associated Polyposis (MAP), yet this process remains poorly understood. This study aimed to identify genes that are mutated in FAP and MAP duodenal adenomas and to characterise the cellular consequences for duodenal tumorigenesis.
2023-08-07 | GSE189035 | GEO
Project description:Variants of uncertain significance (VUS) limit the actionability of genetic testing. A prominent example is MUTYH, a base excision repair factor associated with polyposis and colorectal cancer, which has a pathogenic variant carrier rate approaching 1 in 50 individuals in some populations. To systematically interrogate variant function in MUTYH, we coupled deep mutational scanning with a DNA repair reporter containing its lesion substrate, 8OG:A. Our variant-to-function map covers >97% of all possible MUTYH point variants (n=10,941) and achieves 100% accuracy classifying pathogenicity of known clinical variants (n=247). Leveraging a large clinical registry, we observe significant associations with colorectal polyps and cancer, with more severely impaired missense variants conferring greater risk. We recapitulate known functional differences between pathogenic founder mutations and highlight sites of complete missense intolerance, including residues that intercalate DNA and coordinate essential Zn2+ or Fe-S clusters. This map provides a resource to resolve the 1,122 existing clinical missense VUS in MUTYH and demonstrates a scalable strategy to interrogate other clinically relevant DNA repair factors.
2025-03-01 | GSE290379 | GEO
Project description:Mice with MUTYH-null allele (Mutyh+/-, Mutyh-/-) were fed a high-fat/high-cholesterol (HFHC) diet or HFHC + high iron diet. The incidence of liver tumors and histological features of the liver were compared. We used microarray to examine the gene expression patterns associated with hepatocarcinogenesis in our model.
2020-08-31 | GSE157142 | GEO
Project description:MUTYH is a base excision repair enzyme, it plays a crucial role in the correction of DNA errors from guanine oxidation and may be considered a cell protective factor. In humans it is an adenine DNA glycosylase that removes adenine misincorporated in 7,8-dihydro-8-oxoguanine (8-oxoG) pairs, inducing G:C to T:A transversions. MUTYH functionally cooperates with OGG1 that eliminates 8-oxodG derived from excessive reactive oxygen species production. MUTYH mutations have been linked to MUTYH associated polyposis syndrome (MAP), an autosomal recessive disorder characterized by multiple colorectal adenomas. MAP patients show a greatly increased lifetime risk for gastrointestinal cancers. The cancer risk in mono-allelic carriers associated with one MUTYH mutant allele is controversial and it remains to be clarified whether the altered functions of this protein may have a pathophysiological involvement in other diseases besides familial gastrointestinal diseases. This review evaluates the role of MUTYH, focusing on current studies of human neoplastic and non-neoplastic diseases different to colon polyposis and colorectal cancer. This will provide novel insights into the understanding of the molecular basis underlying MUTYH-related pathogenesis. Furthermore, we describe the association between MUTYH single nucleotide polymorphisms (SNPs) and different cancer and non-cancer diseases. We address the utility to increase our knowledge regarding MUTYH in the light of recent advances in the literature with the aim of a better understanding of the potential for identifying new therapeutic targets. Considering the multiple functions and interactions of MUTYH protein, its involvement in pathologies based on oxidative stress damage could be hypothesized. Although the development of extraintestinal cancer in MUTYH heterozygotes is not completely defined, the risk for malignancies of the duodenum, ovary, and bladder is also increased as well as the onset of benign and malignant endocrine tumors. The presence of MUTYH pathogenic variants is an independent predictor of poor prognosis in sporadic gastric cancer and in salivary gland secretory carcinoma, while its inhibition has been shown to reduce the survival of pancreatic ductal adenocarcinoma cells. Furthermore, some MUTYH SNPs have been associated with lung, hepatocellular and cervical cancer risk. An additional role of MUTYH seems to contribute to the prevention of numerous other disorders with an inflammatory/degenerative basis, including neurological and ocular diseases. Finally, it is interesting to note that MUTYH could be a new therapeutic target and future studies will shed light on its specific functions in the prevention of diseases and in the improvement of the chemo-sensitivity of cancer cells.
| S-EPMC7407923 | biostudies-literature
Project description:MUTYH Associated Polyposis (MAP), a Polyposis predisposition caused by biallelic mutations in the Base Excision Repair (BER) gene MUTYH, confers a marked risk of colorectal cancer (CRC). The MAP phenotype is difficult to distinguish from other hereditary CRC syndromes. Especially from Familial Adenomatous Polyposis (FAP) and to a lesser extend Lynch Syndrome, which are caused by germline mutations in the APC and Mismatch Repair (MMR) genes, respectively.Here we review research findings regarding MUTYH interactions, genotypic and phenotypic characteristics of MAP, as well as surveillance and treatment of the disease. The applied papers, published between 1/1 2002- 1/2 2008, were found through PubMed.The exact role of MUTYH in CRC tumorgenesis is still uncertain, although MAP tumors show distinct molecular features, including somatic G:C>T:A transversions in the APC gene. Furthermore, cooperation between the BER and the MMR systems exists, as MUTYH interacts with MMR gene-products. Possibly, monoallelic defects in both pathways are of significance to CRC development.Specific MUTYH variants are found to be characteristic in distinct ethnic populations, which could facilitate future genetic screening. Knowledge concerning functional consequences of many MUTYH germline mutations remains sparse. Most thoroughly investigated are the two most common MUTYH variants, Y179C and G396D, both generating dysfunctional gene products.PHENOTYPIC FEATURES OF MAP INCLUDE: development of 10-100 colorectal adenomas, debuting at 46-47 years, often CRC at time of clinical diagnosis, and in some, development of extracolonic manifestations.
| S-EPMC2691665 | biostudies-literature
Project description:Oxidative stress is a major risk factor for Alzheimer’s disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegeneration. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoguanine accumulation in DNA. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoguanine in DNA. MUTYH is reported to actively contribute to the neurodegenerative process in Parkinson and Huntington diseases and some mouse models of neurodegenerative diseases by accelerating neuronal dysfunction and microgliosis under oxidative conditions; however, whether or not MUTYH is involved in AD pathogenesis remains unclear. In the present study, we examined the contribution of MUTYH to the AD pathogenesis. Using postmortem human brains, we showed that various types of MUTYH transcripts and proteins are expressed in most hippocampal neurons and glia in both non-AD and AD brains. We further introduced MUTYH deficiency into AppNL-G-F/NL-G-F knock-in AD model mice, which produce humanized toxic amyloid-β without the overexpression of APP protein, and investigated the effects of MUTYH deficiency on the behavior, pathology, gene expression, and neurogenesis. MUTYH deficiency improved memory impairment in AppNL-G-F/NL-G-F mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to the phagocytic activity of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MUTYH, which is expressed in the hippocampus of AD patients as well as non-AD subjects, actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis.
2021-12-23 | GSE157766 | GEO
Project description:Studying whether removal of base-excision repair from mitochondria will result into increase in mitochondrial DNA (mtDNA) mutation load. The endogenous genes of OGG1 and MUTYH DNA glycosylases were modified to lack the genomic region encoding for the predicted mitochondrial targeting sequence. The mouse lines used: A mouse line that lacks the region encoding for the mitochondrial targeting sequence (L2 to W23) of OGG1 (Ogg1 dMTS mice). A mouse line that lacks the region encoding the mitochondrial targeting sequence (K2 to P33) of MUTYH (Mutyh dMTS mice). To accumulate mutations to the mitochondrial DNA these mice were bred double homozygous Mutyh dMTS x Ogg1 dMTS mice as a maternal lineage for five consecutive generations and mitochondrial DNA from liver was extracted from the offspring and sequenced with Illumina. OGG1 and MUTYH are involved in repair of 8-oxo-dG from DNA. 8-oxo-dG can be a mutagenic lesion because some DNA repair polymerases are known to erroneously incorporate adenosine opposite to 8-oxo-dG during replication leading to GC>TA transversion mutations.
2018-07-13 | E-MTAB-6532 | biostudies-arrayexpress
Project description:Gastric adenocarcinoma and proximal polyposis of the stomach is an autosomal dominant cancer predisposition syndrome of fundic gland polyposis with a significant risk of gastric adenocarcinoma. We mapped the gene to 5q22 and found loss of heterozygosity (LOH) only on 5q in fundic gland polyps from affected individuals. Sanger sequencing revealed novel point mutations in APC promoter 1B that co-segregated with disease. All three mutations reduced binding of YY1, and all three mutations showed abrogated activity of the APC promoter 1B luciferase assays. Whole genome sequencing of fundic gland polyps without 5q LOH identified somatic truncating mutations in APC.
2016-08-01 | GSE73547 | GEO
Project description:Oxidative DNA damage has been associated with cognitive decline. The Ogg1 and Mutyh DNA glycosylases cooperate to prevent mutations caused by 8-oxoG, a major premutagenic oxidative DNA base lesion. Here, we have examined behavior and cognitive function in mice deficient of these glycosylases. We found that Ogg1-/-Mutyh-/- mice were more active and less anxious and that their learning ability was impaired. In contrast, Mutyh-/- mice showed moderately improved memory compared to WT. There was no change in genomic 8-oxoG levels, suggesting that Ogg1 and Mutyh play minor roles in global repair in adult brain. Notably, transcriptome analysis of hippocampus revealed that differentially expressed genes in the mutant mice belong to pathways known to be involved in anxiety and cognitive function. Thus, beyond their involvement in DNA repair, Ogg1 and Mutyh modulate cognitive function and behavior, and related hippocampal gene expression, suggesting a novel role for 8-oxoG in regulating adaptive behavior.
2015-12-20 | GSE73029 | GEO