MUTYH (mutY homolog (E. coli))

2006-06-01 Maurizio Genuardi , Rossella Tricarico Affiliation

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

Identity

HGNC

MUTYH

LOCATION

1p34.1

LOCUSID

4595

ALIAS

MYH

FUSION GENES

Show Gene Fusions

DNA/RNA

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

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

Article Bibliography

Pubmed ID	Last Year	Title	Authors
11818965	2002	Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors.	Al-Tassan N et al
15673720	2005	Functional 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
15523092	2004	Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.	Croitoru ME et al
14999774	2004	Prevalence 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
11801590	2002	Human 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
12707038	2003	Germline mutations but not somatic changes at the MYH locus contribute to the pathogenesis of unselected colorectal cancers.	Halford SE et al
12393807	2002	Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-->T:A mutations.	Jones S et al
15083190	2004	Increased frequency of the k-ras G12C mutation in MYH polyposis colorectal adenomas.	Jones S et al
14633673	2003	Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway.	Lipton L et al
15290654	2004	The multiple colorectal adenoma phenotype and MYH, a base excision repair gene.	Lipton L et al
7823963	1995	Characterization of a mammalian homolog of the Escherichia coli MutY mismatch repair protein.	McGoldrick JP et al
10684930	2000	Identification 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
14618256	2003	Human MutY: gene structure, protein functions and interactions, and role in carcinogenesis.	Parker AR et al
12966098	2003	Defective human MutY phosphorylation exists in colorectal cancer cell lines with wild-type MutY alleles.	Parker AR et al
15987719	2005	Cells with pathogenic biallelic mutations in the human MUTYH gene are defective in DNA damage binding and repair.	Parker AR et al
15661655	2005	Insight 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
16042573	2005	MutYH (MYH) and colorectal cancer.	Sampson JR et al
12606733	2003	Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH.	Sieber OM et al
15188161	2004	High 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 ID	Transcript ID	Uniprot
ENSG00000132781	ENST00000354383	Q9UIF7
ENSG00000132781	ENST00000354383	E5KP28
ENSG00000132781	ENST00000355498	Q9UIF7
ENSG00000132781	ENST00000372098	Q9UIF7
ENSG00000132781	ENST00000372098	E5KP26
ENSG00000132781	ENST00000372104	Q9UIF7
ENSG00000132781	ENST00000372110	Q9UIF7
ENSG00000132781	ENST00000372115	Q9UIF7
ENSG00000132781	ENST00000372115	E5KP27
ENSG00000132781	ENST00000412971	Q5T418
ENSG00000132781	ENST00000435155	Q5T413
ENSG00000132781	ENST00000448481	Q9UIF7
ENSG00000132781	ENST00000450313	E5KP25
ENSG00000132781	ENST00000456914	Q9UIF7
ENSG00000132781	ENST00000461495	E9PI11
ENSG00000132781	ENST00000467459	H0YEI2
ENSG00000132781	ENST00000467940	E9PP30
ENSG00000132781	ENST00000470256	E9PMH1
ENSG00000132781	ENST00000475516	E9PIW5
ENSG00000132781	ENST00000481571	E9PI11
ENSG00000132781	ENST00000483127	E9PP34
ENSG00000132781	ENST00000485271	H0YCA8
ENSG00000132781	ENST00000488731	E9PNY0
ENSG00000132781	ENST00000525160	E9PKM9
ENSG00000132781	ENST00000528013	E9PM53
ENSG00000132781	ENST00000529892	H0YCY5
ENSG00000132781	ENST00000529984	E9PNY0
ENSG00000132781	ENST00000531105	E9PLT4
ENSG00000132781	ENST00000533178	H0YER6
ENSG00000132781	ENST00000672818	E5KP26

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Base excision repair	KEGG	ko03410
Base excision repair	KEGG	hsa03410
DNA Repair	REACTOME	R-HSA-73894
Base Excision Repair	REACTOME	R-HSA-73884
Base-Excision Repair, AP Site Formation	REACTOME	R-HSA-73929
Depurination	REACTOME	R-HSA-73927
Recognition and association of DNA glycosylase with site containing an affected purine	REACTOME	R-HSA-110330
Cleavage of the damaged purine	REACTOME	R-HSA-110331
Resolution of Abasic Sites (AP sites)	REACTOME	R-HSA-73933
Displacement of DNA glycosylase by APEX1	REACTOME	R-HSA-110357

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PD	PMIDs
PA445204	Ovarian Neoplasms	Disease	ClinicalAnnotation	associated	PD	24533712
PA449014	cisplatin	Chemical	ClinicalAnnotation	associated	PD	24533712
PA449165	cyclophosphamide	Chemical	ClinicalAnnotation	associated	PD	24533712

References

Pubmed ID	Year	Title	Citations
37589222	2024	Increased KRAS G12C Prevalence, High Tumor Mutational Burden, and Specific Mutational Signatures Are Associated With MUTYH Mutations: A Pan-Cancer Analysis.	0
38062336	2024	Breast cancers in monoallelic MUTYH germline mutation carriers have clinicopathological features overlapping with those in BRCA1 germline mutation carriers.	1
38071180	2024	Multiple colorectal adenomas syndrome: The role of MUTYH mutation and the polyps' number in clinical management and colorectal cancer risk.	0
38394468	2024	Pan-Cancer Interrogation of MUTYH Variants Reveals Biallelic Inactivation and Defective Base Excision Repair Across a Spectrum of Solid Tumors.	0
38790183	2024	Exploring the Role of the MUTYH Gene in Breast, Ovarian and Endometrial Cancer.	0
37589222	2024	Increased KRAS G12C Prevalence, High Tumor Mutational Burden, and Specific Mutational Signatures Are Associated With MUTYH Mutations: A Pan-Cancer Analysis.	0
38062336	2024	Breast cancers in monoallelic MUTYH germline mutation carriers have clinicopathological features overlapping with those in BRCA1 germline mutation carriers.	1
38071180	2024	Multiple colorectal adenomas syndrome: The role of MUTYH mutation and the polyps' number in clinical management and colorectal cancer risk.	0
38394468	2024	Pan-Cancer Interrogation of MUTYH Variants Reveals Biallelic Inactivation and Defective Base Excision Repair Across a Spectrum of Solid Tumors.	0
38790183	2024	Exploring the Role of the MUTYH Gene in Breast, Ovarian and Endometrial Cancer.	0
36245263	2023	Summary of the experiences, knowledge, medical management, and family communication of monoallelic MUTYH carriers.	0
36631987	2023	Structural snapshots of base excision by the cancer-associated variant MutY N146S reveal a retaining mechanism.	3
36979362	2023	Evolutionary Origin of MUTYH Germline Pathogenic Variations in Modern Humans.	3
37749864	2023	A one-stop approach to diagnosing hereditary colorectal cancer in the Chinese population.	0
36245263	2023	Summary of the experiences, knowledge, medical management, and family communication of monoallelic MUTYH carriers.	0

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