Machado-Joseph disease type 3

Summary

Machado-Joseph disease type 3 (MONDO:0017176) is a disease with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 1
• Phenotypes (HPO): 38
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0000590	Progressive external ophthalmoplegia	Very frequent (80-99%)
HP:0002071	Abnormality of extrapyramidal motor function	Very frequent (80-99%)
HP:0002073	Progressive cerebellar ataxia	Very frequent (80-99%)
HP:0008944	Distal lower limb amyotrophy	Very frequent (80-99%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0007089	Facial-lingual fasciculations	Frequent (30-79%)
HP:0007240	Progressive gait ataxia	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0011960	Substantia nigra gliosis	Frequent (30-79%)
HP:0040140	Degeneration of the striatum	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0000623	Supranuclear ophthalmoplegia	Frequent (30-79%)
HP:0000640	Gaze-evoked nystagmus	Frequent (30-79%)
HP:0000651	Diplopia	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002198	Dilated fourth ventricle	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0002366	Abnormal lower motor neuron morphology	Frequent (30-79%)
HP:0002398	Degeneration of anterior horn cells	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002493	Upper motor neuron dysfunction	Frequent (30-79%)
HP:0002503	Spinocerebellar tract degeneration	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003457	EMG abnormality	Frequent (30-79%)
HP:0000011	Neurogenic bladder	Occasional (5-29%)
HP:0001605	Vocal cord paralysis	Occasional (5-29%)
HP:0001751	Abnormal vestibular function	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0003477	Peripheral axonal neuropathy	Occasional (5-29%)
HP:0004370	Abnormality of temperature regulation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Machado-Joseph disease type 3
Mondo ID	MONDO:0017176
Orphanet	276244
ICD-11	1540439031
SNOMED CT	91955005
UMLS	C0751670
MedGen	155611
GARD	0021050
Is cancer (heuristic)	no

Also known as: azorean disease, type iii · SCA3, Machado type · spinocerebellar ataxia type 3, Machado type

Data availability: 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › Huntington disease and related disorders › Huntington disease-like syndrome › Machado-Joseph disease › Machado-Joseph disease type 3

Related subtypes (3): Machado-Joseph disease type 1, Machado-Joseph disease type 2, Machado-Joseph disease type 4

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ATXN3	Definitive	Autosomal dominant	Machado-Joseph disease	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATXN3	Orphanet:276238	Machado-Joseph disease type 1
ATXN3	Orphanet:276241	Machado-Joseph disease type 2
ATXN3	Orphanet:276244	Machado-Joseph disease type 3

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATXN3	HGNC:7106	ENSG00000066427	P54252	Ataxin-3	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATXN3	Ataxin-3	Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATXN3	Other/Unknown	no		UIM_dom, Josephin, Ataxin-3

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
colonic epithelium	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATXN3	269	ubiquitous	marker	calcaneal tendon, colonic epithelium, tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATXN3	3,125

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATXN3	P54252	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Josephin domain DUBs	1	951.7×	0.009	ATXN3
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	380.7×	0.009	ATXN3
FOXO-mediated transcription	1	335.9×	0.009	ATXN3
Deubiquitination	1	124.1×	0.018	ATXN3
RNA Polymerase II Transcription	1	22.5×	0.072	ATXN3
Post-translational protein modification	1	19.2×	0.072	ATXN3
Gene expression (Transcription)	1	17.8×	0.072	ATXN3
Generic Transcription Pathway	1	15.1×	0.074	ATXN3
Metabolism of proteins	1	12.4×	0.081	ATXN3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein localization to cytosolic proteasome complex	1	16852.0×	0.001	ATXN3
regulation of cell-substrate adhesion	1	5617.3×	0.002	ATXN3
monoubiquitinated protein deubiquitination	1	1872.4×	0.004	ATXN3
cellular response to misfolded protein	1	1404.3×	0.004	ATXN3
intermediate filament cytoskeleton organization	1	936.2×	0.004	ATXN3
positive regulation of ERAD pathway	1	887.0×	0.004	ATXN3
protein quality control for misfolded or incompletely synthesized proteins	1	766.0×	0.004	ATXN3
exploration behavior	1	648.1×	0.004	ATXN3
protein K48-linked deubiquitination	1	648.1×	0.004	ATXN3
protein K63-linked deubiquitination	1	624.1×	0.004	ATXN3
positive regulation of ubiquitin-dependent protein catabolic process	1	561.7×	0.004	ATXN3
nucleotide-excision repair	1	383.0×	0.005	ATXN3
cellular response to heat	1	343.9×	0.005	ATXN3
negative regulation of TORC1 signaling	1	324.1×	0.005	ATXN3
cellular response to amino acid starvation	1	318.0×	0.005	ATXN3
protein deubiquitination	1	177.4×	0.008	ATXN3
microtubule cytoskeleton organization	1	121.2×	0.011	ATXN3
actin cytoskeleton organization	1	79.1×	0.015	ATXN3
chemical synaptic transmission	1	77.3×	0.015	ATXN3
ubiquitin-dependent protein catabolic process	1	74.2×	0.015	ATXN3
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.020	ATXN3
nervous system development	1	45.9×	0.022	ATXN3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATXN3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ATXN3	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ATXN3

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ATXN3	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford