WDR48 (WD repeat domain 48)

2017-04-01 Anne Olazabal-Herrero , Godefridus J Peters , Elisa Giovannetti , Jose Antonio Rodriguez Affiliation

Identity

HGNC

WDR48

LOCATION

3p22.2 (Starts at 39051986 and ends at 39096671 bp from pter (according to hg-38))

IMAGE

LEGEND

Figure 1: Localization of WDR48 on chromosome 3p22.2. WDR48 starts from 39051986 and ends at 39096671 bp.

LOCUSID

57599

ALIAS

Bun62,P80,SPG60,UAF1

FUSION GENES

Show Gene Fusions

Abstract

WDR48 is a WD40-repeat containing protein that regulates the activity of three human deubiquitinating enzymes: USP1, USP12 and USP46. The best characterized role of WDR48 is regulation of the DNA damage response in complex with USP1. The USP1\/WDR48 complex promotes deubiquitination of monoubiquitinated FANCD2 and monoubiquitinated PCNA, which are required in the regulation of translesion synthesis (TLS) and Fanconi anemia (FA) DNA repair pathways, respectively. In addition, in complex with USP12 and USP46, WDR48 regulates other important cellular processes such as synaptic transmission or signalling through the Akt, Notch and T-cell receptor pathways.

DNA/RNA

Description

WDR48 gene is located on chromosome 3 in the region p22.2. WDR48 was first cloned in 2000 (Nagase et al., 2000) as a gene coding for a 607 amino acid protein called KIAA1449. In 2002, Park and co-workers (Park et al., 2002) cloned the full-length cDNA encoding the 677 amino acid WDR48 protein, which they called p80.

Transcription

Ten alternatively spliced transcript variants have been identified (WDR48-001, -003, -004, -005, -006, -007, -008, -009, -010 and -011) for this gene. Transcription variants -001 and -008 encode for proteins containing 677 and 162 amino acids, respectively. The remaining variants are not translated into a protein product.

Pseudogene

Not reported pseudogenes. Paralogs for WDR48 are STRN4 and STRN3.

Mutations

Somatic

A survey in the COSMIC mutation database (accession date: 17 November 2016) revealed a total of 71 mutations that lead to different modification in different human tumors. Most of the modifications are missense mutations whose functional consequences need to be addressed (Table 1).
Table 1: Cancer-associated mutations in WDR48. The table shows a detailed list of WDR48 cancer-associated mutations reported to date (November 2016) in the COSMIC mutation database, including the DNA modification (CDS Mutation), protein modification (AA mutation) and affected tissue. Missense amino acid substitutions are indicated in black, nonsense amino acid substitution in red and frameshift insertion/deletions in blue. Synonymous amino acid substitutions have been omitted.

CDS Mutation	AA mutation	Tissue
c.8C>T	p.A3V	Skin
c.35 36GG>>AA	p.R12Q	Skin
c.43G>T	p.V15L	Urinary tract
c.53C>T	p.S18F	Skin
c.56A>G	p.Y19C	Haematopoietic and lymphoid
c.64C>T	p.R22*	Endometrium
c.83A>G	p.Y28C	Large intestine
c.88C>T	p.R30*	Large intestine
c.113C>T	p.L45F	NS
c.148C>T	p.R50*	Large intestine
c.175G>A	p.V59I	NS
c.189G>T	p.K63N	Upper aerodigestive tract
c.206C>T	p.A69V	Stomach
c.221A>G	p.H74R	Stomach
c. 277G>T	p.A93S	Autonomic ganglia
c.284C>T	p.S95F	Prostate
c.290C>T	p.T97M	Oesophagus
c. 304T>C	p.W102R	Breast
c.317A>G	p.K106R	Oesophagus
c.330G>T	p.M110I	Skin
c.374_375insT	p.A126fs*4	Oesophagus
c.403G>T	p.A135S	Liver
c.504A>C	p.K168N	Large intestine
c.565G>A	p.E189K	Breast
c.585G>T	p.W195C	Stomach
c.610A>G	p.M204V	Haematopoietic and lymphoid
c.659G>C	p.R220T	Oesophagus
c.668C>T	p.T223M	Large intestine
c.682G>T	p.G228C	Small intestine
c.703C>T	p.R235C	Large intestine
c.745C>T	p.R249*	Large intestine
c.746G>T	p.R249L	Liver
c.770C>T	p.A257V	Prostate
c.784G>A	p.D262N	Cervix
c.859C>T	p.R287W	Skin
c.871T>G	p.C291G	Endometrium
c.916G>T	p.A306S	Endometrium
c.934A>G	p.I312V	Breast
c.1001C>T	p.A334V	Stomach
c.1006G>T	p.G336*	Liver
c.1007G>C	p.G33A	Urinary tract
c.1024T>A	p.C342S	Central nervous system
c.1036A>G	p.I346V	Upper aerodigestive tract
c.1102A>G	p.I368V	Haematopoietic and lymphoid
c.1210G>A	p.E404K	Cervix
c.1326G>T	p.W442C	Large intestine
c.1343C>A	p.A448D	Endometrium
c.1343C>T	p.A448V	Prostate
c.1345G>A	p.G449S	Pancreas
c.1434_1435insTG	p.V479fs*2	Biliary tract
c.1141C>T	p.P481S	Skin
c.1451A>G	p.E484G	Pancreas
c.1486C>A	p.Q496K	Haematopoietic and lymphoid
c.1495C>T	p.R499*	Endometrium
c.1508_1524del17	p.N504fs*10	Ovary
c.1522C>T	p.Q508*	Skin
c.1543G>T	p.V515L	Urinary tract
c.1567C>T	p.R523C	Skin
c.1682A>G	p.K561R	Large intestine and Pancreas
c.1705C>T	p.L569F	Skin
c.1743A>C	p.K581N	Lung
c.1740delA	p.D583fs*75	Biliary tract
c.1812T>G	p.I604M	Large intestine
c.1858G>A	p.E620K	Urinary tract
c.1870G>A	p.E624K	Large intestine and Urinary tract
c.1895C>T	p.A632V	Endometrium
c.1963C>T	p.R655*	Stomach
c.1969G>A	p.V657M	Skin
c.1989G>C	p.K663N	Lung
c.1999G>A	p.D667N	Skin
c.2017C>T	p.R673C	Breast

Implicated in

Entity name

Fanconi anaemia

Note

In mice, knockout of WDR48 results is a phenotype that resembles the phenotype of human patients with Fanconi anemia (FA) (Park et al., 2013), a rare genetic disease characterized by congenital malformations, progressive bone marrow failure, genomic instability, hypersensitivity to DNA cross-linking agents and increased susceptibility to cancer (Kee and DAndrea 2012).

Entity name

Autosomal recessive spastic paraplegia type 60 (SPG60)

Note

Hereditary spastic paraplegias (HSP) are rare neurodegenerative disorders. The main pathological characteristic is the degeneration of the corticospinal tracts. Novarino and co-workers (Novarino et al., 2014) identified homozygosity for a WDR48 deletion mutant (c.1879_1881delAAG), resulting in a deletion of glutamic acid at position 628 (E628del), in a single individual from a consanguineous family that leads to spastic paraplegia type 60. The contribution of this variant to SPG60 has not been confirmed.

Bibliography

Pubmed ID	Last Year	Title	Authors

Other Information

Locus ID:

NCBI: 57599
MIM: 612167
HGNC: 30914
Ensembl: ENSG00000114742

Variants:

dbSNP: 57599
ClinVar: 57599
TCGA: ENSG00000114742
COSMIC: WDR48

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000114742	ENST00000302313	Q8TAF3
ENSG00000114742	ENST00000302313	A0A024R2L1
ENSG00000114742	ENST00000413099	F8W7Y5
ENSG00000114742	ENST00000420940	F8W9K4
ENSG00000114742	ENST00000423296	F8W7Q3
ENSG00000114742	ENST00000433841	F8W6P2
ENSG00000114742	ENST00000441361	C9JC24

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
Fanconi anemia pathway	KEGG	ko03460
Fanconi anemia pathway	KEGG	hsa03460
Metabolism of proteins	REACTOME	R-HSA-392499
Post-translational protein modification	REACTOME	R-HSA-597592
Deubiquitination	REACTOME	R-HSA-5688426
Ub-specific processing proteases	REACTOME	R-HSA-5689880

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
19075014	2009	UAF1 is a subunit of multiple deubiquitinating enzyme complexes.	81
20147737	2010	WDR20 regulates activity of the USP12 x UAF1 deubiquitinating enzyme complex.	41
18032488	2008	Human papillomavirus E1 helicase interacts with the WD repeat protein p80 to promote maintenance of the viral genome in keratinocytes.	26
24145035	2013	WD repeat protein WDR48 in complex with deubiquitinase USP12 suppresses Akt-dependent cell survival signaling by stabilizing PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1).	24
23116119	2012	Serine phosphorylation is critical for the activation of ubiquitin-specific protease 1 and its interaction with WD40-repeat protein UAF1.	15
27373336	2016	Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20.	13
24850727	2014	E1-mediated recruitment of a UAF1-USP deubiquitinase complex facilitates human papillomavirus DNA replication.	11
27463890	2016	The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair.	11
22278251	2012	Inhibition of human papillomavirus DNA replication by an E1-derived p80/UAF1-binding peptide.	8
22701671	2012	Two nuclear localization signals in USP1 mediate nuclear import of the USP1/UAF1 complex.	8

Citation

Anne Olazabal-Herrero ; Godefridus J Peters ; Elisa Giovannetti ; Jose Antonio Rodriguez

WDR48 (WD repeat domain 48)

Atlas Genet Cytogenet Oncol Haematol. 2017-04-01

Online version: http://atlasgeneticsoncology.org/gene/53058/img/tumors-explorer/