Classic dopamine transporter deficiency syndrome

Summary

Classic dopamine transporter deficiency syndrome (MONDO:0054835) is a disease caused by SLC6A3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: SLC6A3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 46

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	classic dopamine transporter deficiency syndrome
Mondo ID	MONDO:0054835
OMIM	613135
DOID	DOID:0070489
NCIT	C129866
SNOMED CT	722763000
UMLS	C5700336
MedGen	1814585
GARD	0025981
Is cancer (heuristic)	no

Also known as: classic DTDS · Parkinsonism-dystonia, infantile, 1 · PKDYS · PKDYS1

Data availability: 46 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › parkinsonism-dystonia, infantile › classic dopamine transporter deficiency syndrome

Related subtypes (2): brain dopamine-serotonin vesicular transport disease, parkinsonism-dystonia 3, childhood-onset

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

46 retrieved; paginated sample, class counts are floors:

19 uncertain significance, 7 benign, 5 benign/likely benign, 5 pathogenic, 5 conflicting classifications of pathogenicity, 3 likely pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
16763	NM_001044.5(SLC6A3):c.1103T>A (p.Leu368Gln)	SLC6A3	Pathogenic	no assertion criteria provided
16764	NM_001044.5(SLC6A3):c.1184C>T (p.Pro395Leu)	SLC6A3	Pathogenic	no assertion criteria provided
2499597	NM_001044.5(SLC6A3):c.1569_1592delinsA (p.Cys523_Phe531delinsTer)	SLC6A3	Pathogenic	criteria provided, single submitter
29685	NM_001044.5(SLC6A3):c.1269+1G>A	SLC6A3	Pathogenic	criteria provided, multiple submitters, no conflicts
97017	NM_001044.5(SLC6A3):c.671T>C (p.Leu224Pro)	SLC6A3	Pathogenic	no assertion criteria provided
4813769	NM_001044.5(SLC6A3):c.1708dup (p.Ala570fs)	SLC6A3	Likely pathogenic	criteria provided, single submitter
931466	NM_001044.5(SLC6A3):c.1398+5G>A	SLC6A3	Likely pathogenic	criteria provided, single submitter
97016	NM_001044.5(SLC6A3):c.1031+1G>A	SLC6A3	Likely pathogenic	criteria provided, single submitter
290889	NM_001044.5(SLC6A3):c.1676C>T (p.Ala559Val)	SLC6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
377082	NM_001044.5(SLC6A3):c.499C>T (p.Leu167Phe)	SLC6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
538065	NM_001044.5(SLC6A3):c.1155C>T (p.Asp385=)	SLC6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
807497	NM_001044.5(SLC6A3):c.178C>T (p.Arg60Trp)	SLC6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
97018	NM_001044.5(SLC6A3):c.1561C>T (p.Arg521Trp)	SLC6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1019641	NC_000005.9:g.(?1394830)(1394893_?)dup	SLC6A3	Uncertain significance	criteria provided, single submitter
1022175	NM_001044.5(SLC6A3):c.898G>A (p.Val300Ile)	SLC6A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1408732	NM_001044.5(SLC6A3):c.580C>T (p.Pro194Ser)	SLC6A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1444993	NM_001044.5(SLC6A3):c.431C>T (p.Thr144Met)	SLC6A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1507933	NM_001044.5(SLC6A3):c.149C>T (p.Pro50Leu)	SLC6A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2436069	NM_001044.5(SLC6A3):c.217G>A (p.Val73Ile)	SLC6A3	Uncertain significance	criteria provided, single submitter
2499598	NM_001044.5(SLC6A3):c.792+4A>T	SLC6A3	Uncertain significance	criteria provided, single submitter
2585508	NM_001044.5(SLC6A3):c.1504G>A (p.Gly502Arg)	SLC6A3	Uncertain significance	criteria provided, single submitter
3065418	NM_001044.5(SLC6A3):c.655C>T (p.Arg219Cys)	SLC6A3	Uncertain significance	criteria provided, single submitter
3362541	NM_001044.5(SLC6A3):c.1075TCC[1] (p.Ser360del)	SLC6A3	Uncertain significance	criteria provided, single submitter
3391326	NM_001044.5(SLC6A3):c.1403G>T (p.Gly468Val)	SLC6A3	Uncertain significance	criteria provided, single submitter
4080116	NM_001044.5(SLC6A3):c.1850G>C (p.Trp617Ser)	SLC6A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
4080117	NM_001044.5(SLC6A3):c.411A>G (p.Ile137Met)	SLC6A3	Uncertain significance	criteria provided, single submitter
4080118	NM_001044.5(SLC6A3):c.47C>G (p.Ala16Gly)	SLC6A3	Uncertain significance	criteria provided, single submitter
538067	NM_001044.5(SLC6A3):c.70G>A (p.Val24Met)	SLC6A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
634445	NM_001044.5(SLC6A3):c.1067C>T (p.Thr356Met)	SLC6A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
851586	NM_001044.5(SLC6A3):c.1603G>A (p.Val535Met)	SLC6A3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
SLC6A3	Definitive	Autosomal recessive	classic dopamine transporter deficiency syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC6A3	Orphanet:238455	Infantile dystonia-parkinsonism

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
SLC6A3	HGNC:11049	ENSG00000142319	Q01959	Sodium-dependent dopamine transporter	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC6A3	Sodium-dependent dopamine transporter	Mediates sodium- and chloride-dependent transport of dopamine.

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)
SLC6A3	Other/Unknown	no		Na/ntran_symport, Na/ntran_symport_dopamine, SNS_sf

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
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
substantia nigra	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC6A3	84	tissue_specific	marker	substantia nigra, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC6A3	2,245

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC6A3	Q01959	17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Defective neurotransmitter clearance by SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS)	1	11420.0×	6e-04	SLC6A3
Defective transport of neurotransmitters by SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS)	1	11420.0×	6e-04	SLC6A3
Dopamine clearance from the synaptic cleft	1	5710.0×	8e-04	SLC6A3
Neurotransmitter clearance	1	1268.9×	0.003	SLC6A3
SLC-mediated transport of neurotransmitters	1	407.9×	0.006	SLC6A3
SLC transporter disorders	1	203.9×	0.010	SLC6A3
R-HSA-425366	1	181.3×	0.010	SLC6A3
Disorders of transmembrane transporters	1	139.3×	0.012	SLC6A3
Transmission across Chemical Synapses	1	76.1×	0.019	SLC6A3
SLC-mediated transmembrane transport	1	59.2×	0.022	SLC6A3
Neuronal System	1	44.3×	0.027	SLC6A3
Transport of small molecules	1	25.1×	0.043	SLC6A3
Disease	1	13.1×	0.076	SLC6A3

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
adenohypophysis development	1	2407.4×	0.002	SLC6A3
hyaloid vascular plexus regression	1	2407.4×	0.002	SLC6A3
dopamine uptake	1	2106.5×	0.002	SLC6A3
dopamine biosynthetic process	1	1872.4×	0.002	SLC6A3
dopamine uptake involved in synaptic transmission	1	1872.4×	0.002	SLC6A3
regulation of dopamine metabolic process	1	1685.2×	0.002	SLC6A3
dopamine catabolic process	1	1685.2×	0.002	SLC6A3
obsolete dopamine transport	1	1532.0×	0.002	SLC6A3
obsolete monoamine transport	1	1203.7×	0.002	SLC6A3
prepulse inhibition	1	1123.5×	0.002	SLC6A3
response to iron ion	1	936.2×	0.002	SLC6A3
response to cocaine	1	581.1×	0.003	SLC6A3
response to cAMP	1	510.7×	0.003	SLC6A3
positive regulation of multicellular organism growth	1	495.6×	0.003	SLC6A3
neurotransmitter transport	1	421.3×	0.003	SLC6A3
lactation	1	421.3×	0.003	SLC6A3
response to nicotine	1	421.3×	0.003	SLC6A3
amino acid transport	1	312.1×	0.004	SLC6A3
cognition	1	285.6×	0.004	SLC6A3
sodium ion transmembrane transport	1	203.0×	0.006	SLC6A3
locomotory behavior	1	179.3×	0.006	SLC6A3
sensory perception of smell	1	156.0×	0.007	SLC6A3
response to ethanol	1	146.5×	0.007	SLC6A3
response to xenobiotic stimulus	1	69.1×	0.014	SLC6A3

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SLC6A3	CETIRIZINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC6A3	466	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CETIRIZINE	4	SLC6A3
BEPRIDIL	4	SLC6A3
CANDESARTAN CILEXETIL	4	SLC6A3
BEXAROTENE	4	SLC6A3
CLOTRIMAZOLE	4	SLC6A3
AMINOCAPROIC ACID	4	SLC6A3
SIMVASTATIN	4	SLC6A3
NABUMETONE	4	SLC6A3
PROPIVERINE	4	SLC6A3
ACETOPHENAZINE	4	SLC6A3
MESORIDAZINE	4	SLC6A3
VALPROIC ACID	4	SLC6A3
NIRAPARIB	4	SLC6A3
INDACATEROL	4	SLC6A3
IMIPRAMINE	4	SLC6A3
HALOFANTRINE	4	SLC6A3
RIMONABANT	4	SLC6A3
ARIPIPRAZOLE	4	SLC6A3
AMOXAPINE	4	SLC6A3
IDARUBICIN	4	SLC6A3
DESVENLAFAXINE	4	SLC6A3
EZETIMIBE	4	SLC6A3
SAQUINAVIR	4	SLC6A3
PONATINIB	4	SLC6A3
DESLORATADINE	4	SLC6A3
AFATINIB	4	SLC6A3
DULOXETINE	4	SLC6A3
PEMOLINE	4	SLC6A3
CELECOXIB	4	SLC6A3
UMECLIDINIUM	4	SLC6A3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC6A3	1,043	Binding:993, Functional:24, ADMET:24, Toxicity:2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SLC6A3	1,043

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

30 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)
CETIRIZINE	4	SLC6A3
BEPRIDIL	4	SLC6A3
CANDESARTAN CILEXETIL	4	SLC6A3
BEXAROTENE	4	SLC6A3
CLOTRIMAZOLE	4	SLC6A3
AMINOCAPROIC ACID	4	SLC6A3
SIMVASTATIN	4	SLC6A3
NABUMETONE	4	SLC6A3
PROPIVERINE	4	SLC6A3
ACETOPHENAZINE	4	SLC6A3
MESORIDAZINE	4	SLC6A3
VALPROIC ACID	4	SLC6A3
NIRAPARIB	4	SLC6A3
INDACATEROL	4	SLC6A3
IMIPRAMINE	4	SLC6A3
HALOFANTRINE	4	SLC6A3
RIMONABANT	4	SLC6A3
ARIPIPRAZOLE	4	SLC6A3
AMOXAPINE	4	SLC6A3
IDARUBICIN	4	SLC6A3
DESVENLAFAXINE	4	SLC6A3
EZETIMIBE	4	SLC6A3
SAQUINAVIR	4	SLC6A3
PONATINIB	4	SLC6A3
DESLORATADINE	4	SLC6A3
AFATINIB	4	SLC6A3
DULOXETINE	4	SLC6A3
PEMOLINE	4	SLC6A3
CELECOXIB	4	SLC6A3
UMECLIDINIUM	4	SLC6A3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SLC6A3
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.