USP8

protein-coding

ubiquitin specific peptidase 8, the group of Ubiquitin specific peptidases

Gene summary

This gene encodes a protein that belongs to the ubiquitin-specific processing protease family of proteins. The encoded protein is thought to regulate the morphology of the endosome by ubiquitination of proteins on this organelle and is involved in cargo sorting and membrane trafficking at the early endosome stage. This protein is required for the cell to enter the S phase of the cell cycle and also functions as a positive regulator in the Hedgehog signaling pathway in development. Pseudogenes of this gene are present on chromosomes 2 and 6. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

MANE transcript

NM_005154.5

Inheritance

AD, AR

ClinVar variants

P:4U:95B:56

Top phenotype

autosomal recessive spastic paraplegia type 59

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr15:50,424,380-50,514,421

External References & Databases

Ensembl (ENSG00000138592)

Transcript & Mutation Effects

hg38 • Region Span ~90.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

hereditary spastic paraplegiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019064

Submitter: Ambry Genetics

hereditary spastic paraplegiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0019064

Submitter: PanelApp Australia

autosomal recessive spastic paraplegia type 59SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018416

Submitter: Orphanet

genetic developmental and epileptic encephalopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to USP8 variants in ClinVar

6 Conditions Cataloged

Hereditary spastic paraplegiaTotal: 156

not providedTotal: 31

USP8-related disorderTotal: 8

Pituitary dependent hypercortisolismTotal: 5

Autosomal recessive spastic paraplegia type 59Total: 1

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005154.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	41 clinvar	4 clinvar	47
missense	3 clinvar		86 clinvar	3 clinvar	8 clinvar	100
nonsense	1 clinvar		2 clinvar			3
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	4	0	95	44	12	155

Highest pathogenic variant AF is 6.84046e-7

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 73 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005154.5	RefSeq	NP_005145.3	19	MANE Select
ENST00000307179.9	Ensembl	ENSP00000302239.4	19	MANE Select
NM_001128610.3	RefSeq	NP_001122082.1	19	Standard
NM_001283049.2	RefSeq	NP_001269978.1	16	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
usp8	Danio rerio	Structure: motor neuron Quality: branched abnormal

Gene / Model

Organism

Observed Phenotype

usp8

Danio rerio

Structure: motor neuron

Quality: branched

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cushing,s syndrome - Homo sapiens (human)
Endocytosis - Homo sapiens (human)
Mitophagy - animal - Homo sapiens (human)
EGF-EGFR Signaling Pathway
Signaling by WNT

Biological Process

mitotic cytokinesis
ubiquitin-dependent protein catabolic process
endosome organization
Ras protein signal transduction
cell population proliferation

Molecular Function

cysteine-type endopeptidase activity
thiol-dependent ubiquitin-specific protease activity
protein binding
SH3 domain binding
cadherin binding

Cellular Component

nucleus
cytoplasm
early endosome
cytosol
postsynaptic density

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000433963
Coding exons: 19
Length: 76704
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125731
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.87	439	564	0.779	0.0000289	7316
Missense (PolyPhen)		188	299.06	0.62864		4036
Synonymous	1.00	176	194	0.908	0.00000951	2073
Loss of Function	6.66	2	55.6	0.0360	0.00000286	736

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000034	0.000029	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000036	0.000035	rare
South Asian	0	0.0	absent
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation. Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the M phase. Involved in cell proliferation. Required to enter into S phase in response to serum stimulation. May regulate T-cell anergy mediated by RNF128 via the formation of a complex containing RNF128 and OTUB1. Probably regulates the stability of STAM2 and RASGRF1. Regulates endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early endosomes, and maintenance of ESCRT-0 stability. The level of protein ubiquitination on endosomes is essential for maintaining the morphology of the organelle. Deubiquitinates EPS15 and controles tyrosine kinase stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR degradation and downstream MAPK signaling. Involved in acrosome biogenesis through interaction with the spermatid ESCRT-0 complex and microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1. {ECO:0000269|PubMed:16520378, ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:18329369, ECO:0000269|PubMed:9628861}.;
Disease: DISEASE: Pituitary adenoma 4, ACTH-secreting (PITA4) [MIM:219090]: A form of pituitary adenoma, a neoplasm of the pituitary gland and one of the most common neuroendocrine tumors. Pituitary adenomas are clinically classified as functional and non-functional tumors, and manifest with a variety of features, including local invasion of surrounding structures and excessive hormone secretion. Functional pituitary adenomas are further classified by the type of hormone they secrete. PITA4 results in excessive production of adrenocorticotropic hormone. This leads to hypersecretion of cortisol by the adrenal glands and ACTH-dependent Cushing syndrome. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:28505279}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.121

Intolerance Scores

LoFtool: 0.379
RVIS EVS: 0.4
RVIS percentile EVS: 76.45

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.603

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium