Dystonia 22, juvenile-onset

Summary

Dystonia 22, juvenile-onset (MONDO:0957539) is a disease caused by TSPOAP1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TSPOAP1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dystonia 22, juvenile-onset
Mondo ID	MONDO:0957539
OMIM	620453
DOID	DOID:0060966
UMLS	C5830645
MedGen	1841281
GARD	0026859
Is cancer (heuristic)	no

Data availability: 6 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › extrapyramidal and movement disease › dystonic disorder › inherited dystonia › dystonia 22, juvenile-onset

Related subtypes (23): lymphatic malformation 5, Woodhouse-Sakati syndrome, severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome, torsion dystonia 7, developmental malformations-deafness-dystonia syndrome, dopa-responsive dystonia due to sepiapterin reductase deficiency, ataxia - oculomotor apraxia type 4, striatonigral degeneration, childhood-onset, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, dystonia 28, childhood-onset, isolated dystonia, combined dystonia, dystonia 30, dystonia 31, dystonia 32, dystonia 33, dystonia 34, myoclonic, dystonia 35, childhood-onset, familial idiopathic torsion dystonia, dystonia, focal, task-specific, dystonia 37, early-onset, with striatal lesions, dystonia 22, adult-onset, autosomal dominant dopa-responsive dystonia

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

ClinVar germline variants

6 retrieved; paginated sample, class counts are floors:

3 likely pathogenic, 2 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2574616	NM_004758.4(TSPOAP1):c.538del (p.Ala180fs)	TSPOAP1	Pathogenic	no assertion criteria provided
2574617	NM_004758.4(TSPOAP1):c.2449_2450inv (p.Gln817Ter)	TSPOAP1	Pathogenic	no assertion criteria provided
3338456	GRCh37/hg19 7p22.1(chr7:5521357-5569119)x1	ACTB	Likely pathogenic	no assertion criteria provided
4070522	NM_004758.4(TSPOAP1):c.3172dup (p.Arg1058fs)	TSPOAP1	Likely pathogenic	criteria provided, single submitter
4849373	NM_004758.4(TSPOAP1):c.5134_5141dup (p.Glu1715fs)	TSPOAP1	Likely pathogenic	criteria provided, single submitter
3582371	NM_004758.4(TSPOAP1):c.4744G>A (p.Gly1582Arg)	TSPOAP1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 6 · 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
TSPOAP1	Strong	Autosomal recessive	dystonia 22, juvenile-onset	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSPOAP1	Orphanet:101150	Autosomal recessive dopa-responsive dystonia
ACTB	Orphanet:2995	Baraitser-Winter cerebrofrontofacial syndrome
ACTB	Orphanet:64755	Becker nevus syndrome
ACTB	Orphanet:673556	Pseudomyogenic hemangioendothelioma
ACTB	Orphanet:674653	Actinomyopathy-associated syndromic thrombocytopenia
ACTB	Orphanet:79107	Developmental malformations-deafness-dystonia syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TSPOAP1	HGNC:16831	ENSG00000005379	O95153	Peripheral-type benzodiazepine receptor-associated protein 1	gencc,clinvar
ACTB	HGNC:132	ENSG00000075624	P60709	Actin, cytoplasmic 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSPOAP1	Peripheral-type benzodiazepine receptor-associated protein 1	Required for synaptic transmission regulation.
ACTB	Actin, cytoplasmic 1	Actin is a highly conserved protein that polymerizes to produce filaments that form cross-linked networks in the cytoplasm of cells.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSPOAP1	Antibody/Immunoglobulin	yes		SH3_domain, FN3_dom, Ig-like_fold
ACTB	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
right frontal lobe	1
right uterine tube	1
postcentral gyrus	1
saphenous vein	1
urethra	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSPOAP1	253	broad	marker	right uterine tube, right frontal lobe, granulocyte
ACTB	295	ubiquitous	marker	urethra, postcentral gyrus, saphenous vein

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTB	2,212
TSPOAP1	708

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTB	P60709	88

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TSPOAP1	O95153	57.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 106. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Folding of actin by CCT/TriC	1	571.0×	0.017	ACTB
Formation of annular gap junctions	1	519.1×	0.017	ACTB
GBP-mediated host defense	1	519.1×	0.017	ACTB
Gap junction degradation	1	475.8×	0.017	ACTB
Regulation of CDH1 Function	1	475.8×	0.017	ACTB
Pregnenolone biosynthesis	1	407.9×	0.017	TSPOAP1
Acetylcholine Neurotransmitter Release Cycle	1	335.9×	0.017	TSPOAP1
Cell-extracellular matrix interactions	1	335.9×	0.017	ACTB
Formation of the non-canonical BAF (ncBAF) complex	1	335.9×	0.017	ACTB
Serotonin Neurotransmitter Release Cycle	1	317.2×	0.017	TSPOAP1
Norepinephrine Neurotransmitter Release Cycle	1	317.2×	0.017	TSPOAP1
Formation of the canonical BAF (cBAF) complex	1	317.2×	0.017	ACTB
Formation of the polybromo-BAF (pBAF) complex	1	317.2×	0.017	ACTB
Formation of the embryonic stem cell BAF (esBAF) complex	1	300.5×	0.017	ACTB
Dopamine Neurotransmitter Release Cycle	1	248.3×	0.017	TSPOAP1
Gap junction trafficking and regulation	1	237.9×	0.017	ACTB
Gap junction trafficking	1	237.9×	0.017	ACTB
Glutamate Neurotransmitter Release Cycle	1	228.4×	0.017	TSPOAP1
Global Genome Nucleotide Excision Repair (GG-NER)	1	228.4×	0.017	ACTB
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	228.4×	0.017	ACTB
Signaling by RAS mutants	1	211.5×	0.017	ACTB
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	203.9×	0.017	ACTB
Prefoldin mediated transfer of substrate to CCT/TriC	1	196.9×	0.017	ACTB
Interaction between L1 and Ankyrins	1	184.2×	0.017	ACTB
Regulation of endogenous retroelements	1	184.2×	0.017	ACTB
Positive epigenetic regulation of rRNA expression	1	173.0×	0.017	ACTB
RHO GTPases activate IQGAPs	1	173.0×	0.017	ACTB
Parasite infection	1	173.0×	0.017	ACTB
Leishmania phagocytosis	1	173.0×	0.017	ACTB
RHO GTPases Activate WASPs and WAVEs	1	158.6×	0.017	ACTB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of norepinephrine uptake	1	8426.0×	0.002	ACTB
cellular response to cytochalasin B	1	8426.0×	0.002	ACTB
regulation of norepinephrine uptake	1	4213.0×	0.003	ACTB
morphogenesis of a polarized epithelium	1	2106.5×	0.003	ACTB
regulation of transepithelial transport	1	2106.5×	0.003	ACTB
protein localization to adherens junction	1	1685.2×	0.004	ACTB
adherens junction assembly	1	648.1×	0.008	ACTB
apical protein localization	1	495.6×	0.009	ACTB
regulation of synaptic vesicle endocytosis	1	443.5×	0.009	ACTB
regulation of neurotransmitter secretion	1	383.0×	0.009	TSPOAP1
regulation of G0 to G1 transition	1	337.0×	0.009	ACTB
regulation of protein localization to plasma membrane	1	324.1×	0.009	ACTB
regulation of nucleotide-excision repair	1	300.9×	0.009	ACTB
regulation of double-strand break repair	1	290.6×	0.009	ACTB
regulation of mitotic metaphase/anaphase transition	1	247.8×	0.009	ACTB
maintenance of blood-brain barrier	1	240.7×	0.009	ACTB
positive regulation of T cell differentiation	1	227.7×	0.009	ACTB
establishment or maintenance of cell polarity	1	200.6×	0.009	ACTB
cell motility	1	200.6×	0.009	ACTB
positive regulation of double-strand break repair via homologous recombination	1	191.5×	0.009	ACTB
substantia nigra development	1	183.2×	0.009	ACTB
positive regulation of myoblast differentiation	1	183.2×	0.009	ACTB
positive regulation of stem cell population maintenance	1	172.0×	0.009	ACTB
positive regulation of double-strand break repair	1	172.0×	0.009	ACTB
platelet aggregation	1	168.5×	0.009	ACTB
regulation of G1/S transition of mitotic cell cycle	1	153.2×	0.009	ACTB
negative regulation of cell differentiation	1	142.8×	0.009	ACTB
positive regulation of cell differentiation	1	133.8×	0.010	ACTB
axonogenesis	1	80.2×	0.015	ACTB
cytoskeleton organization	1	66.3×	0.018	ACTB

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
ACTB	1	2
TSPOAP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	ACTB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ACTB	21	Binding:21
TSPOAP1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	ACTB

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	1	ACTB
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	TSPOAP1
E	Difficult family or no structure, no drug	0

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)
TSPOAP1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.