MUTYH (mutY homolog (E. coli))

2006-06-01   Maurizio Genuardi , Rossella Tricarico 

Department of Clinical Pathophysiology, University of Florence, Viale Gaetano Pieraccini 6, 50139 Firenze, Italy

Identity

HGNC
LOCATION
1p34.1
LOCUSID
ALIAS
MYH
FUSION GENES

DNA/RNA

Atlas Image
Mutyh AUG 1, 2 and 3 are alternative codons for translation initiation; cDNA not drawn to scale (adapted from Parker et al., 2003).

Description

The MUTYH gene contains 16 exons spanning a region of 11147 bp.

Transcription

The transcribed mRNA is 1854 bp long. There are three major classes of human MUTYH mRNAs: a, b and g. Each of these undergoes alternative splicing, suggesting a total of 10 possible mature transcripts. However, their distribution and abundance in different normal tissues have yet to be determined. The reference isoform is MutYa3.

Proteins

Atlas Image
Diagram of the MUTYH protein in scale. Filled boxes represent known functional domains (adapted from Sampson et al, 2005).

Description

Aminoacids: 535. Molecular Weight: 52 kDa. MUTYH is a protein involved in base excision repair (BER). It contains a DNA binding domain, an adenine binding motif and several interaction domains for APE1, PCNA, RPA and MSH6, located in different regions of the gene.

Expression

Ubiquitous.

Localisation

Nuclear and mithocondrial.

Function

MUTYH is involved in oxidative DNA damage repair. Human MutY is responsible for recognition and removal of inappropriately inserted adenine in Ao8-oxoG mispairs. If unrepaired, the Ao8-oxoG mispairs can result in C:G to A:T transversions. MUTYH functions in a postreplication repair pathway and is targeted to the newly synthesized daughter strand of DNA for removal of the adenine base.

Homology

MUTYH is homologous to the bacterial MutY gene, and MUTYH homologues are also present in eukaryote.

Mutations

Germinal

Biallelic germline mutations of MUTYH are associated with colorectal polyposis. The most common mutations in Caucasians are the missense substitutions Y165C (494A>G) and G382D (1145G>A). Functional analysis of C165 and D382 proteins has shown a severe decrease of catalytic activity. E466X and Y90X are the common mutations reported in Indian and Pakistani cases. Several other missense, nonsense, in-frame, frameshift and splicing mutations have been found in patients with colorectal polyposis.

Somatic

To date, no MUTYH somatic mutation has been described.

Implicated in

Entity name
MAP (MUTYH-associated polyposis).
Disease
Biallelic MUTYH mutations are responsible for the autosomal recessive form of intestinal adenomatous polyposis.
Oncogenesis
Defective BER function associated with MUTYH mutations determines an increase in the somatic mutation rate, namely of G>T transversions at guanine residues that are potential targets of oxidative damage. Tumors from biallelic MUTYH mutation carriers display an excess of somatic G>T mutations in the APC and KRAS genes

Bibliography

Pubmed IDLast YearTitleAuthors
118189652002Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors.Al-Tassan N et al
156737202005Functional characterization of two human MutY homolog (hMYH) missense mutations (R227W and V232F) that lie within the putative hMSH6 binding domain and are associated with hMYH polyposis.Bai H et al
155230922004Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.Croitoru ME et al
149997742004Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas.Gismondi V et al
118015902002Human MutY homolog, a DNA glycosylase involved in base excision repair, physically and functionally interacts with mismatch repair proteins human MutS homolog 2/human MutS homolog 6.Gu Y et al
127070382003Germline mutations but not somatic changes at the MYH locus contribute to the pathogenesis of unselected colorectal cancers.Halford SE et al
123938072002Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-->T:A mutations.Jones S et al
150831902004Increased frequency of the k-ras G12C mutation in MYH polyposis colorectal adenomas.Jones S et al
146336732003Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway.Lipton L et al
152906542004The multiple colorectal adenoma phenotype and MYH, a base excision repair gene.Lipton L et al
78239631995Characterization of a mammalian homolog of the Escherichia coli MutY mismatch repair protein.McGoldrick JP et al
106849302000Identification of human MutY homolog (hMYH) as a repair enzyme for 2-hydroxyadenine in DNA and detection of multiple forms of hMYH located in nuclei and mitochondria.Ohtsubo T et al
146182562003Human MutY: gene structure, protein functions and interactions, and role in carcinogenesis.Parker AR et al
129660982003Defective human MutY phosphorylation exists in colorectal cancer cell lines with wild-type MutY alleles.Parker AR et al
159877192005Cells with pathogenic biallelic mutations in the human MUTYH gene are defective in DNA damage binding and repair.Parker AR et al
156616552005Insight into the functional consequences of hMYH variants associated with colorectal cancer: distinct differences in the adenine glycosylase activity and the response to AP endonucleases of Y150C and G365D murine MYH.Pope MA et al
160425732005MutYH (MYH) and colorectal cancer.Sampson JR et al
126067332003Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH.Sieber OM et al
151881612004High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis.Venesio T et al

Other Information

Locus ID:

NCBI: 4595
MIM: 604933
HGNC: 7527
Ensembl: ENSG00000132781

Variants:

dbSNP: 4595
ClinVar: 4595
TCGA: ENSG00000132781
COSMIC: MUTYH

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000132781ENST00000354383Q9UIF7
ENSG00000132781ENST00000354383E5KP28
ENSG00000132781ENST00000355498Q9UIF7
ENSG00000132781ENST00000372098Q9UIF7
ENSG00000132781ENST00000372098E5KP26
ENSG00000132781ENST00000372104Q9UIF7
ENSG00000132781ENST00000372110Q9UIF7
ENSG00000132781ENST00000372115Q9UIF7
ENSG00000132781ENST00000372115E5KP27
ENSG00000132781ENST00000412971Q5T418
ENSG00000132781ENST00000435155Q5T413
ENSG00000132781ENST00000448481Q9UIF7
ENSG00000132781ENST00000450313E5KP25
ENSG00000132781ENST00000456914Q9UIF7
ENSG00000132781ENST00000461495E9PI11
ENSG00000132781ENST00000467459H0YEI2
ENSG00000132781ENST00000467940E9PP30
ENSG00000132781ENST00000470256E9PMH1
ENSG00000132781ENST00000475516E9PIW5
ENSG00000132781ENST00000481571E9PI11
ENSG00000132781ENST00000483127E9PP34
ENSG00000132781ENST00000485271H0YCA8
ENSG00000132781ENST00000488731E9PNY0
ENSG00000132781ENST00000525160E9PKM9
ENSG00000132781ENST00000528013E9PM53
ENSG00000132781ENST00000529892H0YCY5
ENSG00000132781ENST00000529984E9PNY0
ENSG00000132781ENST00000531105E9PLT4
ENSG00000132781ENST00000533178H0YER6
ENSG00000132781ENST00000672818E5KP26

Expression (GTEx)

0
5
10
15
20
25
30
35
40

Pathways

PathwaySourceExternal ID
Base excision repairKEGGko03410
Base excision repairKEGGhsa03410
DNA RepairREACTOMER-HSA-73894
Base Excision RepairREACTOMER-HSA-73884
Base-Excision Repair, AP Site FormationREACTOMER-HSA-73929
DepurinationREACTOMER-HSA-73927
Recognition and association of DNA glycosylase with site containing an affected purineREACTOMER-HSA-110330
Cleavage of the damaged purineREACTOMER-HSA-110331
Resolution of Abasic Sites (AP sites)REACTOMER-HSA-73933
Displacement of DNA glycosylase by APEX1REACTOMER-HSA-110357

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA445204Ovarian NeoplasmsDiseaseClinicalAnnotationassociatedPD24533712
PA449014cisplatinChemicalClinicalAnnotationassociatedPD24533712
PA449165cyclophosphamideChemicalClinicalAnnotationassociatedPD24533712

References

Pubmed IDYearTitleCitations
123938072002Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-->T:A mutations.88
166090222006Polymorphisms in genes of nucleotide and base excision repair: risk and prognosis of colorectal cancer.71
159315962005Germline susceptibility to colorectal cancer due to base-excision repair gene defects.61
159315962005Germline susceptibility to colorectal cancer due to base-excision repair gene defects.61
118015902002Human MutY homolog, a DNA glycosylase involved in base excision repair, physically and functionally interacts with mismatch repair proteins human MutS homolog 2/human MutS homolog 6.58
192458652009Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.53
192458652009Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.53
155230922004Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.50
155230922004Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.50
197327752009Expanded extracolonic tumor spectrum in MUTYH-associated polyposis.50

Citation

Maurizio Genuardi ; Rossella Tricarico

MUTYH (mutY homolog (E. coli))

Atlas Genet Cytogenet Oncol Haematol. 2006-06-01

Online version: http://atlasgeneticsoncology.org/gene/41464/mutyh