Inherited dystonia

Summary

Inherited dystonia (MONDO:0044807) is a disease (an umbrella term covering 24 Mondo subtypes) caused by ARFGEF3 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: ARFGEF3 (GenCC Strong)
• Umbrella term: 24 Mondo subtypes
• Cohort genes: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	inherited dystonia
Mondo ID	MONDO:0044807
OMIM	128100
Orphanet	391799
NCIT	C35527
UMLS	C5680022
MedGen	1842468
GARD	0021630
Is cancer (heuristic)	no

Also known as: familial dystonia · hereditary dystonic disorder · rare genetic dystonia · rare genetic dystonic disorder

Data availability: 3 GenCC gene-disease records.

Disease family

An umbrella term covering 24 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › extrapyramidal and movement disease › dystonic disorder › inherited dystonia

Related subtypes (7): focal dystonia, multifocal dystonia, segmental dystonia, hemidystonia-hemiatrophy syndrome, nocturnal paroxysmal dystonia, idiopathic torsion dystonia, torsion dystonia

Subtypes (24): 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, juvenile-onset, 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
ARFGEF3	Strong	Autosomal dominant	inherited dystonia
ATP5F1B	Moderate	Autosomal dominant	inherited dystonia	3
CIZ1	Moderate	Unknown	dystonia 23	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CIZ1	Orphanet:420492	Adult-onset cervical dystonia, DYT23 type

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CIZ1	HGNC:16744	ENSG00000148337	Q9ULV3	Cip1-interacting zinc finger protein	gencc
ARFGEF3	HGNC:21213	ENSG00000112379	Q5TH69	Brefeldin A-inhibited guanine nucleotide-exchange protein 3	gencc
ATP5F1B	HGNC:830	ENSG00000110955	P06576	ATP synthase F(1) complex subunit beta, mitochondrial	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CIZ1	Cip1-interacting zinc finger protein	May regulate the subcellular localization of CIP/WAF1.
ARFGEF3	Brefeldin A-inhibited guanine nucleotide-exchange protein 3	Participates in the regulation of systemic glucose homeostasis, where it negatively regulates insulin granule biogenesis in pancreatic islet beta cells.
ATP5F1B	ATP synthase F(1) complex subunit beta, mitochondrial	Catalytic subunit beta, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport co…

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CIZ1	Transcription factor	no		Matrin/U1-C_Znf_C2H2, Matrin/U1-like-C_Znf_C2H2, Znf_C2H2_type
ARFGEF3	Other/Unknown	no		Sec7_dom, Mon2/Sec7/BIG1-like_HDS, ARM-type_fold
ATP5F1B	Other/Unknown	no		ATPase_F1/V1/A1_a/bsu_nucl-bd, AAA+_ATPase, ATPase_F1/V1/A1_a/bsu_N

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	1
right hemisphere of cerebellum	1
right ovary	1
cerebellar vermis	1
parotid gland	1
substantia nigra pars reticulata	1
apex of heart	1
cardiac ventricle	1
heart left ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CIZ1	281	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, right ovary
ARFGEF3	223	broad	marker	parotid gland, cerebellar vermis, substantia nigra pars reticulata
ATP5F1B	288	ubiquitous	marker	apex of heart, cardiac ventricle, heart left ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP5F1B	6,304
CIZ1	2,160
ARFGEF3	755

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP5F1B	P06576	9
CIZ1	Q9ULV3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARFGEF3	Q5TH69	65.15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 3 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
Formation of ATP by chemiosmotic coupling	1	571.0×	0.011	ATP5F1B
Cristae formation	1	346.1×	0.011	ATP5F1B
Transcriptional activation of mitochondrial biogenesis	1	203.9×	0.011	ATP5F1B
Protein localization	1	190.3×	0.011	ATP5F1B
Mitochondrial protein import	1	167.9×	0.011	ATP5F1B
Mitochondrial biogenesis	1	167.9×	0.011	ATP5F1B
Mitochondrial protein degradation	1	114.2×	0.014	ATP5F1B
Aerobic respiration and respiratory electron transport	1	88.5×	0.016	ATP5F1B
Organelle biogenesis and maintenance	1	66.0×	0.019	ATP5F1B
Metabolism of proteins	1	12.4×	0.086	ATP5F1B
Metabolism	1	11.6×	0.086	ATP5F1B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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 DNA-templated DNA replication initiation	1	2808.7×	0.006	CIZ1
negative regulation of cell adhesion involved in substrate-bound cell migration	1	1404.3×	0.006	ATP5F1B
cellular response to interleukin-7	1	432.1×	0.007	ATP5F1B
maintenance of protein location in nucleus	1	374.5×	0.007	CIZ1
ATP biosynthetic process	1	330.4×	0.007	ATP5F1B
random inactivation of X chromosome	1	312.1×	0.007	CIZ1
regulation of ARF protein signal transduction	1	295.6×	0.007	ARFGEF3
proton motive force-driven ATP synthesis	1	267.5×	0.007	ATP5F1B
regulation of intracellular pH	1	200.6×	0.009	ATP5F1B
positive regulation of blood vessel endothelial cell migration	1	130.6×	0.012	ATP5F1B
generation of precursor metabolites and energy	1	114.6×	0.013	ATP5F1B
proton transmembrane transport	1	104.0×	0.013	ATP5F1B
proton motive force-driven mitochondrial ATP synthesis	1	87.8×	0.014	ATP5F1B
osteoblast differentiation	1	40.4×	0.028	ATP5F1B
lipid metabolic process	1	30.5×	0.035	ATP5F1B
angiogenesis	1	20.8×	0.047	ATP5F1B

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CIZ1	0	0
ARFGEF3	0	0
ATP5F1B	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
ATP5F1B	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	CIZ1, ARFGEF3, ATP5F1B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CIZ1	0	—
ARFGEF3	0	—
ATP5F1B	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.