Dystonia 5

Summary

Dystonia 5 (MONDO:0007495) is a disease caused by GCH1 (GenCC Definitive), with 5 cohort genes and 2 clinical trials.

At a glance

• Causal gene: GCH1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 522
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dystonia 5
Mondo ID	MONDO:0007495
OMIM	128230
DOID	DOID:0090043
SNOMED CT	715768000
UMLS	C1851920
MedGen	342121
GARD	0009817
NORD	1702
Is cancer (heuristic)	no

Also known as: Dopa-responsive dystonia, autosomal dominant · Dopa-responsive dystonia; Segawa syndrome AD · DRD · dystonia 5 · dystonia type 5 · dystonia, DOPA-responsive · dystonia, Dopa-responsive, autosomal dominant · dystonia, DOPA-responsive, with or without hyperphenylalaninemia · dystonia, progressive, with diurnal variation · dystonia-Parkinsonism with diurnal fluctuation · DYT-GCH1 · GTP cyclohydrolase 1-deficient dopa-responsive dystonia · Segawa Syndrome · Segawa syndrome, autosomal dominant

Data availability: 522 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of phenylalanine and tyrosine metabolism › disorder of phenylalanine metabolism › tetrahydrobiopterin metabolic process disease › GTP cyclohydrolase I deficiency › dystonia 5

Related subtypes (2): dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive, GTP cyclohydrolase I deficiency with hyperphenylalaninemia

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

522 retrieved; paginated sample, class counts are floors:

194 uncertain significance, 168 likely benign, 73 pathogenic, 36 conflicting classifications of pathogenicity, 17 likely pathogenic, 13 benign, 12 pathogenic/likely pathogenic, 9 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3061843	GRCh38/hg38 14q22.2-22.3(chr14:53949639-56297420)x1	ATG14	Pathogenic	criteria provided, single submitter
2422501	NC_000014.8:g.(?54410919)(55369403_?)del	BMP4	Pathogenic	criteria provided, single submitter
1070262	NC_000014.8:g.(?55313807)(55313858_?)del	GCH1	Pathogenic	criteria provided, single submitter
1070263	NC_000014.8:g.(?55332039)(55369387_?)del	GCH1	Pathogenic	criteria provided, single submitter
1070688	NM_000161.3(GCH1):c.158G>A (p.Trp53Ter)	GCH1	Pathogenic	criteria provided, single submitter
1199011	NM_000161.3(GCH1):c.578_583del (p.Ile193_Glu195delinsLys)	GCH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334460	NM_000161.3(GCH1):c.728dup (p.Phe244fs)	GCH1	Pathogenic	criteria provided, single submitter
1354621	NM_000161.3(GCH1):c.109G>T (p.Glu37Ter)	GCH1	Pathogenic	criteria provided, single submitter
1419261	NM_000161.3(GCH1):c.212del (p.Leu71fs)	GCH1	Pathogenic	criteria provided, single submitter
1432028	NM_000161.3(GCH1):c.724G>T (p.Glu242Ter)	GCH1	Pathogenic	criteria provided, single submitter
1452723	NM_000161.3(GCH1):c.1A>C (p.Met1Leu)	GCH1	Pathogenic	criteria provided, single submitter
1454629	NC_000014.8:g.(?55312466)(55313868_?)del	GCH1	Pathogenic	criteria provided, single submitter
1454630	NC_000014.8:g.(?55310735)(55313868_?)del	GCH1	Pathogenic	criteria provided, single submitter
1455907	NM_000161.3(GCH1):c.453+2T>G	GCH1	Pathogenic	criteria provided, single submitter
1457490	NM_000161.3(GCH1):c.395_396del (p.Val132fs)	GCH1	Pathogenic	criteria provided, single submitter
1460271	NC_000014.8:g.(?55369019)(55369381_?)del	GCH1	Pathogenic	criteria provided, single submitter
1685843	NM_000161.3(GCH1):c.601G>T (p.Gly201Ter)	GCH1	Pathogenic	criteria provided, single submitter
1685844	NM_000161.3(GCH1):c.510-1G>T	GCH1	Pathogenic	criteria provided, single submitter
1687225	NM_000161.3(GCH1):c.478A>T (p.Lys160Ter)	GCH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803977	NM_000161.3(GCH1):c.287G>A (p.Trp96Ter)	GCH1	Pathogenic	criteria provided, single submitter
2135414	NM_000161.3(GCH1):c.185del (p.Glu62fs)	GCH1	Pathogenic	criteria provided, single submitter
2135615	NM_000161.3(GCH1):c.49del (p.Arg17fs)	GCH1	Pathogenic	criteria provided, single submitter
2135851	NM_000161.3(GCH1):c.626+2T>C	GCH1	Pathogenic	criteria provided, single submitter
2137592	NM_000161.3(GCH1):c.233del (p.Ile78fs)	GCH1	Pathogenic	criteria provided, single submitter
2422499	NC_000014.8:g.(?55310735)(55326474_?)del	GCH1	Pathogenic	criteria provided, single submitter
2444362	NM_000161.3(GCH1):c.544C>T (p.Gln182Ter)	GCH1	Pathogenic	criteria provided, single submitter
265173	NM_000161.3(GCH1):c.631_632del (p.Met211fs)	GCH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2925514	NM_000161.3(GCH1):c.751T>C (p.Ter251Arg)	GCH1	Pathogenic	criteria provided, single submitter
2925519	NM_000161.3(GCH1):c.453+1G>A	GCH1	Pathogenic	criteria provided, single submitter
2925520	NM_000161.3(GCH1):c.-22C>T	GCH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 7 · 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
GCH1	Definitive	Autosomal dominant	dystonia 5	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GCH1	Orphanet:2102	GTP cyclohydrolase I deficiency
GCH1	Orphanet:98808	Autosomal dominant dopa-responsive dystonia
BMP4	Orphanet:139471	Microphthalmia with brain and digit anomalies
BMP4	Orphanet:199306	Cleft lip/palate
BMP4	Orphanet:828	Stickler syndrome
BMP4	Orphanet:93100	Renal agenesis, unilateral
TH	Orphanet:101150	Autosomal recessive dopa-responsive dystonia

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GCH1	HGNC:4193	ENSG00000131979	P30793	GTP cyclohydrolase 1	gencc,clinvar
BMP4	HGNC:1071	ENSG00000125378	P12644	Bone morphogenetic protein 4	clinvar
TH	HGNC:11782	ENSG00000180176	P07101	Tyrosine 3-monooxygenase	clinvar
ATG14	HGNC:19962	ENSG00000126775	Q6ZNE5	Beclin 1-associated autophagy-related key regulator	clinvar
MIR4308	HGNC:38206	ENSG00000265432		microRNA 4308	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GCH1	GTP cyclohydrolase 1	Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs).
BMP4	Bone morphogenetic protein 4	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including neurogenesis, vascular development, angiogenesis and osteogenesis.
TH	Tyrosine 3-monooxygenase	Catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the biosynthesis of catecholamines, dopamine, noradrenaline, and adrenaline.
ATG14	Beclin 1-associated autophagy-related key regulator	Required for both basal and inducible autophagy.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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
Enzyme (other)	3	7.2×	0.010
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GCH1	Enzyme (other)	yes	3.5.4.16	GTP_CycHdrlase_I, GTP_CycHdrlase_I_CS, GTP_CycHdrlase_I_dom
BMP4	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
TH	Enzyme (other)	yes	1.14.16.2	ArAA_hydroxylase, Tyr_3_mOase, ArAA_hydroxylase_Fe/CU_BS
ATG14	Enzyme (other)	yes	2.7.1.137	UV_resistance/autophagy_Atg14
MIR4308	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	2
secondary oocyte	2
type B pancreatic cell	1
pigmented layer of retina	1
rectum	1
retina	1
male germ line stem cell (sensu Vertebrata) in testis	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1
gluteal muscle	1
adrenal tissue	1
liver	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GCH1	275	ubiquitous	marker	secondary oocyte, oocyte, type B pancreatic cell
BMP4	189	ubiquitous	marker	pigmented layer of retina, retina, rectum
TH	147	tissue_specific	marker	substantia nigra pars reticulata, substantia nigra pars compacta, male germ line stem cell (sensu Vertebrata) in testis
ATG14	292	ubiquitous	marker	secondary oocyte, oocyte, gluteal muscle
MIR4308	49		yes	liver, primordial germ cell in gonad, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BMP4	4,425
TH	3,526
GCH1	2,123
ATG14	2,086
MIR4308	0

Intra-cohort edges

A	B	Sources
GCH1	TH	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCH1	P30793	11
TH	P07101	7
ATG14	Q6ZNE5	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BMP4	P12644	79.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Catecholamine biosynthesis	1	713.8×	0.022	TH
Formation of lateral plate mesoderm	1	571.0×	0.022	BMP4
Formation of intermediate mesoderm	1	356.9×	0.022	BMP4
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	1	285.5×	0.022	GCH1
Specification of primordial germ cells	1	219.6×	0.022	BMP4
Kidney development	1	203.9×	0.022	BMP4
Dengue virus modulates apoptosis	1	178.4×	0.022	ATG14
Germ layer formation at gastrulation	1	167.9×	0.022	BMP4
Formation of the nephric duct	1	158.6×	0.022	BMP4
Specification of the neural plate border	1	158.6×	0.022	BMP4
Formation of the ureteric bud	1	124.1×	0.026	BMP4
Formation of paraxial mesoderm	1	102.0×	0.027	BMP4
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	1	98.5×	0.027	ATG14
Elastic fibre formation	1	84.0×	0.030	BMP4
Molecules associated with elastic fibres	1	77.2×	0.030	BMP4
Gastrulation	1	64.9×	0.034	BMP4
Reproduction	1	47.6×	0.043	BMP4
Autophagy	1	37.1×	0.052	ATG14
SARS-CoV-2-host interactions	1	29.7×	0.060	ATG14
Macroautophagy	1	28.8×	0.060	ATG14
Post-translational protein phosphorylation	1	25.0×	0.066	BMP4
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	22.3×	0.069	ATG14
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	21.6×	0.069	BMP4
SARS-CoV-2 Infection	1	20.1×	0.071	ATG14
Class I MHC mediated antigen processing & presentation	1	17.5×	0.078	ATG14
Extracellular matrix organization	1	15.8×	0.083	BMP4
SARS-CoV Infections	1	13.9×	0.091	ATG14
Viral Infection Pathways	1	7.7×	0.154	ATG14
Adaptive Immune System	1	7.5×	0.154	ATG14
Infectious disease	1	6.2×	0.177	ATG14

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dopamine biosynthetic process	2	936.2×	3e-04	GCH1, TH
dopamine biosynthetic process from tyrosine	1	4213.0×	0.003	TH
pteridine-containing compound biosynthetic process	1	4213.0×	0.003	GCH1
intermediate mesodermal cell differentiation	1	4213.0×	0.003	BMP4
positive regulation of cardiac muscle fiber development	1	4213.0×	0.003	BMP4
bronchus development	1	4213.0×	0.003	BMP4
bud dilation involved in lung branching	1	4213.0×	0.003	BMP4
mammary gland formation	1	4213.0×	0.003	BMP4
negative regulation of mesenchymal cell proliferation involved in ureter development	1	4213.0×	0.003	BMP4
negative regulation of glomerulus development	1	4213.0×	0.003	BMP4
regulation of mesodermal cell differentiation	1	4213.0×	0.003	BMP4
negative regulation of metanephric S-shaped body morphogenesis	1	4213.0×	0.003	BMP4
negative regulation of metanephric comma-shaped body morphogenesis	1	4213.0×	0.003	BMP4
heart morphogenesis	2	187.2×	0.003	BMP4, TH
positive regulation of protein phosphorylation	2	138.1×	0.003	BMP4, ATG14
regulation of lung blood pressure	1	2106.5×	0.004	GCH1
tendon cell differentiation	1	2106.5×	0.004	BMP4
epinephrine biosynthetic process	1	2106.5×	0.004	TH
positive regulation of branching involved in lung morphogenesis	1	2106.5×	0.004	BMP4
negative regulation of glomerular mesangial cell proliferation	1	2106.5×	0.004	BMP4
negative regulation of branching involved in ureteric bud morphogenesis	1	2106.5×	0.004	BMP4
positive regulation of primary miRNA processing	1	2106.5×	0.004	BMP4
mesodermal cell fate determination	1	1404.3×	0.005	BMP4
specification of animal organ position	1	1404.3×	0.005	BMP4
regulation of cell fate commitment	1	1404.3×	0.005	BMP4
deltoid tuberosity development	1	1404.3×	0.005	BMP4
positive regulation of nitric-oxide synthase activity	1	1404.3×	0.005	GCH1
trachea development	1	1404.3×	0.005	BMP4
glomerular capillary formation	1	1404.3×	0.005	BMP4
nephric duct formation	1	1404.3×	0.005	BMP4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GCH1	0	0
BMP4	0	0
TH	0	0
ATG14	0	0
MIR4308	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
TH	8	Binding:8
BMP4	2	Binding:2
ATG14	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCH1	3.5.4.16	GTP cyclohydrolase I
TH	1.14.16.2	tyrosine 3-monooxygenase
ATG14	2.7.1.137	phosphatidylinositol 3-kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	3	GCH1, TH, ATG14
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	BMP4, MIR4308

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GCH1	0	—
BMP4	2	—
TH	8	—
ATG14	1	—
MIR4308	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03428009	Not specified	RECRUITING	Dystonia Genotype-Phenotype Correlation
NCT07018271	Not specified	NOT_YET_RECRUITING	A Study on the Use of Sulpegfilgrastim to Prevent the Incidence of Neutropenia With Infection in Newly Diagnosed Non-transplant Multiple Myeloma Patients