GeneBe

ATXN3

protein-coding

ataxin 3, the group of MJD deubiquinating enzymes

Gene summary

Machado-Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by this gene contains (CAG)n repeats in the coding region, and the expansion of these repeats from the normal 12-44 to 52-86 is one cause of Machado-Joseph disease. There is a negative correlation between the age of onset and CAG repeat numbers. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2016]

Previous symbols:
  • SCA3
  • MJD

MANE transcript

NM_004993.6

Inheritance

AD

ClinVar variants

P:1U:50B:13

Top phenotype

Spinocerebellar ataxia 3 (Machado-Joseph disease)

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr14:92,044,496-92,106,621

External References & Databases

Ensembl (ENSG00000066427)NCBI Gene (4287)OMIM (607047)HGNC:7106GenCCUniProt (P54252)AlphaFoldClinVar (ATXN3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~62.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Machado-Joseph diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007182

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Machado-Joseph diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007182

Submitter: Ambry Genetics

Machado-Joseph disease type 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017174

Submitter: Orphanet

Machado-Joseph disease type 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017175

Submitter: Orphanet

Machado-Joseph disease type 3SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017176

Submitter: Orphanet

Machado-Joseph diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007182

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 3 (Machado-Joseph disease)AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 5061839; 865531; 7874163; 7573040; 7496771; 7795637; 7633439; 7561932; 7655453; 8619527; 8640226; 9403486; 11176969; 15457499; 15747371; 20301375; 21555642; 21635785; 22023810Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATXN3 variants in ClinVar

6 Conditions Cataloged
Inborn genetic diseasesTotal: 39
not specifiedTotal: 25
not providedTotal: 12
ATXN3-related disorderTotal: 6
Azorean diseaseTotal: 5
Tip-toe gaitTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004993.6. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
3
clinvar
 5
missense
40
clinvar
2
clinvar
 42
nonsense
1
clinvar
 1
start loss
0
frameshift
1
clinvar
5
clinvar
7
clinvar
1
clinvar
 14
splice donor/acceptor (+/-2bp)
2
clinvar
 2
Total015012164
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 77 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004993.6RefSeqNP_004984.211MANE Select
ENST00000644486.2EnsemblENSP00000496695.111MANE Select
NM_001127696.2RefSeqNP_001121168.110Standard
NM_001127697.3RefSeqNP_001121169.29Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
atxn3Danio rerio

Structure: post-vent region

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Protein processing in endoplasmic reticulum - Homo sapiens (human)
  • Josephin domain DUBs
  • Post-translational protein modification
  • Metabolism of proteins
  • Deubiquitination

Biological Process

  • microtubule cytoskeleton organization
  • nucleotide-excision repair
  • ubiquitin-dependent protein catabolic process
  • protein quality control for misfolded or incompletely synthesized proteins
  • chemical synaptic transmission

Molecular Function

  • RNA polymerase II regulatory region DNA binding
  • histone deacetylase activity
  • thiol-dependent ubiquitin-specific protease activity
  • protein binding
  • ubiquitin protein ligase binding

Cellular Component

  • nucleus
  • nucleoplasm
  • nucleolus
  • cytoplasm
  • mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000393287
Coding exons
11
Length
48070
Individuals with no LoFs
112988
Homozygous LoFs
727
Heterozygous LoFs
12033
Defined
125748
p
0.0521
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.351361880.7230.000009282373
Missense (PolyPhen)1537.2960.40219519
Synonymous1.215264.40.8080.00000321625
Loss of Function3.53726.70.2620.00000140291

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0720.064notable
Latino/Admixed American0.0340.029notable
Ashkenazi Jewish0.0480.043notable
East Asian0.110.11notable
Finnish0.0510.045notable
European (Non-Finnish)0.0440.041notable
South Asian0.0970.092notable
Other0.0520.048notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates (PubMed:12297501, PubMed:17696782, PubMed:23625928, PubMed:28445460, PubMed:16118278). Binds long polyubiquitin chains and trims them, while it has weak or no activity against chains of 4 or less ubiquitins (PubMed:17696782). Involved in degradation of misfolded chaperone substrates via its interaction with STUB1/CHIP: recruited to monoubiquitinated STUB1/CHIP, and restricts the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension (By similarity). Interacts with key regulators of transcription and represses transcription: acts as a histone-binding protein that regulates transcription (PubMed:12297501). Regulates autophagy via the deubiquitination of 'Lys-402' of BECN1 leading to the stabilization of BECN1 (PubMed:28445460). {ECO:0000250|UniProtKB:Q9CVD2, ECO:0000269|PubMed:12297501, ECO:0000269|PubMed:16118278, ECO:0000269|PubMed:17696782, ECO:0000269|PubMed:23625928, ECO:0000269|PubMed:28445460}.;
Disease
DISEASE: Spinocerebellar ataxia 3 (SCA3) [MIM:109150]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to cerebellum degeneration with variable involvement of the brainstem and spinal cord. SCA3 belongs to the autosomal dominant cerebellar ataxias type I (ADCA I) which are characterized by cerebellar ataxia in combination with additional clinical features like optic atrophy, ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy and dementia. The molecular defect in SCA3 is the a CAG repeat expansion in ATX3 coding region. Longer expansions result in earlier onset and more severe clinical manifestations of the disease. {ECO:0000269|PubMed:7874163}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.348

Intolerance Scores

LoFtool
0.895
RVIS EVS
0.28
RVIS percentile EVS
71.27

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.974

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyHighMediumHigh
CancerHighHighHigh
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