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MUTYH associated polyposis

Written2006-05Maartje Nielsen, Frederik J. Hes
Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands

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Atlas_Id 10121
Genes implicated inMUTYH  
Inheritance MUTYH associated polyposis (MAP) is an autosomal recessive disorder, the frequency of heterozygotes carriers is 1-2% and the frequency of bi-allelic mutation carriers (according to Hardy-Weinberg equilibrium) lies between 1 per 10.000 and 40.000 newborns.


Phenotype and clinics
  • The penetrance for colon polyps is close to 100% and bi-allelic MUTYH mutation carriers generally develop 10-100's adenomatous polyps/adenomas of the colon and the rectum.
  • Approximately one third of patients also develop polyps/adenomas in the upper gastrointestinal tract.
  • Neoplastic risk
  • Duodenum carcinoma reported in a minority (2 out of 50 MAP patients in the Netherlands).
  • Treatment
  • Colorectal screening, colonoscopy, starting from the age 20-25 years, every 2years.
  • Upper gastrointestinal tract screening from the age of 25-30 years, depending of the stage of identified tumours (Spigelman stadia), follow-up every 1-5 years.
  • In case the number of polyps is too large to be endoscopically removed, subtotal colectomy is indicated.
  • Prognosis When frequent colorectal and upper gastrointestinal tract screening is performed in a MAP-patient who has not developed (colorectal) carcinoma, the change of developing (colorectal) carcinoma is small and prognosis will be comparable to that of a healthy population.
    In MAP patients who have developed colorectal carcinoma, survival will depend on the age of diagnosis and (Dukes) stage of the colorectal carcinoma.

    Other findings

    Note In heterozygous MUTYH mutation carriers a (slight) increased risk for developing colorectal carcinoma has been found. A large case control research showed a relative risk of 1,5 for CRC in MUTYH heterozygous carriers aged > 55 years. Recently a ~3 fold increased risk in heterozygous carriers was found in a study based on relatives of MAP patients, which was significant in persons aged > 55 years and non-significant in persons aged < 55 years. So far, there is no conclusive evidence justifying colonoscopic screening in heterozygous MUTYH carriers.

    A suggested explanation for the relative absence of tumor growth at other places in MAP-patients is that oxidation is a more common effect in the digestive system and that the APC-gene has more sequences (AGAA or TGAA motifs, see heading somatic mutations) which are relatively dependent of MUTYH oxidative damage repair.

    Genes involved and Proteins

    Alias hMYH MutY homolog MYHbeta
    Location 1p34.1 1p32.1-p34.3
    Description The MUTYH gene is composed of 16 exons and 15 introns.
    Transcription The MUTYH gene encodes 11,4 kb, and the open reading frame consists of 1854 bp.
    Description The full-length MUTYH protein contains 546 amino acids (60-65kDa). For mutation description the coding sequence is described and used, which differs because of the absence of 11 codons in exon 3.
    DESCRIPTION Alternative splicing generates a gene product of 521 amino Acids, referred as type 2. Type 1 is transported to the mitochondria, while type 2 lacks the first exon containing a mitochondrial targeting signal (MTS) and is transported to nucleus.
    Expression Expression of MUTYH has been found among others in the digestive system, germ cells, thymus,(rat-) brain, (mouse-) liver and (canine-) myocardium. Probably, the MUTYH protein is expressed widely, because the production of reactive oxygen species (ROS) leading to oxidative damage is generated during normal cellular oxygen metabolism and by oxygen stress conditions in all cells.
    Localisation MUTYH is located in the nucleus and mitochondria.
    Function MUTYH recognizes an oxoG:A mismatch and subsequently excises the undamaged adenine base using a base flipping mechanism. To a lesser extent also G:A, C:A, 8-oxoG:G and 8-oxoA:G mispairs are recognised and catalysed by MUTYH. The MUTYH protein consists of different functional domains. The N-terminal domain on the 5' side contains the catalytic region and includes a helix hairpin helix (HhH), pseudo HhH and an iron sulfur cluster loop motif, which are also common motifs in other BER glycosylases. The C-terminal domain on the 3' side is shares homology with MTH1 and plays a role in 8-oxoG recognition.
    Homology The percentage of similarity between the human muty gene (MUTYH) and that of various organisms is: 99% in chimpanzee, 80% in dog, 79% in mouse, 77% in rat, 66% in chicken and 41% in E.coli.
    Germinal About thirty pathogenic mutations in the MUTYH gene have been described; predominantly missense mutations, but to a lesser extent also small deletions, small insertions, (putative) splice site mutations and one gross deletion. Most common mutations found (in Western population) are the Tyr165Cys (Y165C) and Gly382Asp (G382D), which compromise about 70-75% of mutations in Western MAP patients.
    Other common mutations are: A371fs (c.1105delC, sometimes referred to as 1103delC); c.891+3A>C; P391L in Dutch patients (14%); Glu466del (c.1395delGGA) in Italian and the E466X in Indian people.
    The Y165C mutation is located in the pseudo HhH region that is involved in mismatch specificity and flipping of the adenine into the base specificity pocket. The G382D is located in the C-terminal domain involved in 8-oxoG recognition. In functional tests especially the Y165C, but also the G382D variants, have shown to be devoid of glycosylase activity directed towards 8-oxoG:A. The corresponding variant of G382D in mice, G365D, does not suppress the elevated spontaneous mutations in MUTHY-null ES cells and failed to prevent OGG1 from excising 8-oxo G opposite the generated AP site-which would then result in double strand DNA breaks.

    Recently, the 1105 delC variant showed significantly lowered binding and cleavage activities with heteroduplex oligonucleotides containing A:8-oxoG and 8-oxoA:G mispairs.
    Several SNP's (single nucleotide polymorphism) with amino acid substitutions have been registered in the NCBI database. Most frequently found in cases and controls: His 324Gln (Q324H) in 40-45% and IVS6+ 35 (462 +35) G>A in 20-25%. Pathogenic significance of the V22M SNP is disputed; it's prevalence in controls and in cases is comparable (10-15%).


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    This paper should be referenced as such :
    Nielsen, M ; Hes, F
    MUTYH associated polyposis
    Atlas Genet Cytogenet Oncol Haematol. 2006;10(4):295-299.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :

    External links

    Other database/diseases/10805/myh-associated-polyposis Autosomal recessive familial adenomatous polyposis (GARD)
    Genes implicated inMUTYH   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  

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