DDC

Summary

DDC (dopa decarboxylase, HGNC:2719) is a protein-coding gene on chromosome 7p12.2-p12.1, encoding Aromatic-L-amino-acid decarboxylase (P20711). Catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine and L-5-hydroxytryptophan to serotonin.

The encoded protein catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine. Defects in this gene are the cause of aromatic L-amino-acid decarboxylase deficiency (AADCD). AADCD deficiency is an inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency. Multiple alternatively spliced transcript variants encoding different isoforms have been identified for this gene.

Source: NCBI Gene 1644 — RefSeq curated summary.

At a glance

• Gene–disease (curated): aromatic L-amino acid decarboxylase deficiency (Definitive, ClinGen)
• GWAS associations: 16
• Clinical variants (ClinVar): 668 total — 47 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 62
• Druggable target: yes
• MANE Select transcript: NM_001082971

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2719
Approved symbol	DDC
Name	dopa decarboxylase
Location	7p12.2-p12.1
Locus type	gene with protein product
Status	Approved
Aliases	AADC
Ensembl gene	ENSG00000132437
Ensembl biotype	protein_coding
OMIM	107930
Entrez	1644

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 36 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000357936, ENST00000380984, ENST00000420203, ENST00000426377, ENST00000430300, ENST00000431062, ENST00000444124, ENST00000444733, ENST00000489162, ENST00000494914, ENST00000495320, ENST00000615193, ENST00000617822, ENST00000622873, ENST00000897736, ENST00000897737, ENST00000897738, ENST00000897739, ENST00000897740, ENST00000897741, ENST00000897742, ENST00000897743, ENST00000897744, ENST00000897745, ENST00000897746, ENST00000897747, ENST00000897748, ENST00000897749, ENST00000897750, ENST00000897751, ENST00000897752, ENST00000897753, ENST00000897754, ENST00000897755, ENST00000897756, ENST00000897757, ENST00000897758, ENST00000962221, ENST00000962222, ENST00000962223

RefSeq mRNA: 7 — MANE Select: NM_001082971 NM_000790, NM_001082971, NM_001242886, NM_001242887, NM_001242888, NM_001242889, NM_001242890

CCDS: CCDS5511, CCDS56485, CCDS56486, CCDS56487, CCDS75598, CCDS75599

Canonical transcript exons

ENST00000444124 — 15 exons

Exon	Start	End
ENSE00000905215	50503993	50504059
ENSE00001210749	50499148	50499242
ENSE00001282238	50543885	50544113
ENSE00001649937	50565285	50565405
ENSE00001931857	50458442	50458843
ENSE00003476823	50470073	50470171
ENSE00003493926	50528137	50528280
ENSE00003503203	50467214	50467315
ENSE00003514821	50495350	50495417
ENSE00003531277	50537860	50537979
ENSE00003551837	50476624	50476643
ENSE00003583903	50463213	50463431
ENSE00003583980	50539915	50540028
ENSE00003653854	50529208	50529342
ENSE00003664488	50479787	50479863

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 99.21.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.9200 / max 353.9093, expressed in 123 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84106	1.0749	80
84105	0.8451	55

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.21	gold quality
ileal mucosa	UBERON:0000331	98.84	gold quality
adult organism	UBERON:0007023	97.96	gold quality
kidney epithelium	UBERON:0004819	97.88	gold quality
nephron tubule	UBERON:0001231	97.68	gold quality
renal glomerulus	UBERON:0000074	97.49	gold quality
metanephric glomerulus	UBERON:0004736	97.21	gold quality
adult mammalian kidney	UBERON:0000082	97.11	gold quality
mucosa of transverse colon	UBERON:0004991	96.77	gold quality
duodenum	UBERON:0002114	96.21	gold quality
colonic mucosa	UBERON:0000317	94.93	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.56	gold quality
right lobe of liver	UBERON:0001114	93.57	gold quality
kidney	UBERON:0002113	93.57	gold quality
rectum	UBERON:0001052	93.26	gold quality
liver	UBERON:0002107	90.83	gold quality
small intestine	UBERON:0002108	88.81	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.46	gold quality
metanephros	UBERON:0000081	88.36	gold quality
cortex of kidney	UBERON:0001225	87.97	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.86	silver quality
substantia nigra pars reticulata	UBERON:0001966	85.26	gold quality
buccal mucosa cell	CL:0002336	84.43	gold quality
substantia nigra pars compacta	UBERON:0001965	83.49	gold quality
renal medulla	UBERON:0000362	83.34	gold quality
transverse colon	UBERON:0001157	83.28	gold quality
substantia nigra	UBERON:0002038	82.38	gold quality
body of pancreas	UBERON:0001150	82.36	gold quality
jejunum	UBERON:0002115	82.05	gold quality
midbrain	UBERON:0001891	78.98	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	41.74
E-GEOD-125970	yes	22.20
E-GEOD-137537	yes	20.27
E-CURD-114	yes	11.79
E-HCAD-25	yes	7.43
E-HCAD-10	yes	4.14
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ELF1, EPAS1, FEV, FOXA2, HNF1A, NR4A2, NR5A2, POU3F2, POU4F2, POU5F1

miRNA regulators (miRDB)

31 targeting DDC, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-145-3P	99.33	67.66	764
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-3614-5P	99.30	65.25	837
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-2276-3P	98.76	67.75	1384
HSA-MIR-219A-2-3P	98.62	68.78	797
HSA-MIR-4662A-5P	98.48	67.18	1007
HSA-MIR-3166	98.24	66.63	1223
HSA-MIR-3074-3P	97.83	67.26	922
HSA-MIR-4308	97.56	67.13	1385
HSA-MIR-6500-3P	97.42	67.20	867

Literature-anchored findings (GeneRIF, showing 40)

• gene promoter directs transgene expression to the adult floor plate and aminergic nuclei induced by the isthmus. (PMID:11750071)
• findings suggest that the DDC gene is unlikely to play a major role in the development of autism in our data set (PMID:11992572)
• Results do not support an involvement of the 1-bp or 4-bp deletion within the DDC gene in the etiology of affective disorders. (PMID:12116187)
• DDC might confer susceptibility to bipolar affective disorder predominantly when paternally transmitted (PMID:12555230)
• This enzyme is cloned from and expressed in placenta. (PMID:12718431)
• We report three siblings who showed the clinical phenotype to be caused by aromatic L-amino acid decarboxylase deficiency. Molecular characterization showed a homozygous point mutation (c.387 G–>A) in exon 3. (PMID:14991824)
• Polymorphisms studied do not play a major role in paranoid schizophrenia pathogenesis in the population investigated. (PMID:15318031)
• dopamine decarboxylase mRNA in neuroblastoma patients could be a potential marker for minimal residual disease (PMID:15322424)
• Detection of a new alternative splicing event within the coding region of the human dopa decarboxylase (DDC) mRNA, suggests that the single copy human DDC gene undergoes complex processing leading to the formation of multiple mRNA isoforms. (PMID:15532536)
• Single nucleotide polymorphisms in the dopa decarboxylase gene is associated with nicotine dependence (PMID:15879433)
• Immunohistochemical detection of DOPA decarboxylase shows diffuse staining of Langerhans islets in congenital hyperinsulinism. (PMID:16403819)
• association of alleles and haplotypes at the DOPA decarboxylase (DDC) locus with the DSM-IV diagnosis of nicotine dependence (PMID:16740595)
• Association of the DOPA decarboxylase (DDC) gene on chromosome 7p11 with measures of nicotine dependence. (PMID:17184203)
• Autoantibodies to the COOH-terminal region induce a significant inhibition of enzymatic activity. (PMID:17200166)
• Expands clinical spectrum of AADC deficiency and contributes to the knowledge of the genotype and phenotype correlation for the DDC gene. (PMID:17533144)
• The DDC gene was strongly associated with both adulthood (P=0.00053; odds ratio (OR)=2.17) and childhood ADHD (P=0.0017; OR=1.90) (PMID:17938636)
• study does not support the involvement of tyrosine hydroxylase gene variants as major contributors to suicide, whereas dopa decarboxylase variants could mediate some features related to suicide and be involved in violent suicidal behavior (PMID:17948905)
• analysis of Ddc redefines the imprinted Grb10 domain on mouse proximal chromosome 11 and identifies Ddc_exon1a as the first example of a heart-specific imprinted gene (PMID:17967881)
• Three different mutations were identified in the DDC gene, including two novel mutations 1303 C>T and 1367ins A and one IVS 6+4 A>T mutation in patients with AADC deficiency in Taiwan. (PMID:18567514)
• These data reveal the potential of DDC expression, at the mRNA level, as a novel biomarker in prostate cancer. (PMID:18586020)
• Hhigh expression of DDC both in peripheral blood and bone marrow corresponds to metastatic neuroblastoma at diagnosis, residual disease, and poor outcome. (PMID:18814238)
• The expression of enzymatically active DDC in human leukocytes could indicate a cross-talk between the nervous and the immune systems and raises new questions about the regulatory role of DDC in immune responses. (PMID:19041269)
• No strong evidence was found for the associations between personality and tyrosine or DOPA decarboxylase in comparing healthy and suicide attempted subjects (PMID:19221445)
• AADC was observed in a large number of 5-HT neuronal cell bodies distributed in all of the raphe nuclei,and in the intermediate reticular nucleus, which constitutes the oblique plate of A1/C1 presumptive adrenergic and/or NA neurons. (PMID:19589383)
• DJ-1-dependent activation of dopamine synthesis occurs through interaction of tyrosine hydroxylase and 4-dihydroxy-L-phenylalanine (L-DOPA) decarboxylase with DJ-1 (PMID:19703902)
• The expression of enzymatically active DDC shows the endogenous production of dopamine in U937 cells and raises new questions about the enzyme’s involvement in immune responses. (PMID:19800137)
• The intronic Single Nucleotide Polymorphism at the is significantly associated to the Spielberger State-Trait Anxiety Inventory anxiety scores after multiple testing correction. (PMID:20092830)
• Dopa decarboxylase mRNA expression may be a novel potential tissue biomarker in prognosis of colorectal adenocarcinoma patient survival. (PMID:20424616)
• the human DDC gene undergoes complex processing, leading to the formation of multiple mRNA isoforms in tumor cells (PMID:20535562)
• Normal or increased levels of urinary dopamine are found in the majority of AADC-deficient patientsNormal or increased levels of urinary dopamine are found in the majority of AADC-deficient patients (PMID:20832343)
• Results describe the cellular topology of active human L-dopa decarboxylase. (PMID:21479916)
• we report biochemical and bioinformatic analyses of the human wild-type dopa decarboxylase and the pathogenic variants G102S, F309L, S147R and A275T whose mutations concern amino acid residues at or near the active site. (PMID:21541720)
• In regular smokers, variability at the locus marked by rs3779084 in the dopa decarboxylase gene appears to index biologically based individual differences in the motivation to consume alcohol. (PMID:21797889)
• These results suggested that TonEBP played an important role in the epithelial cells of renal proximal tubule upon hypertonic stress by enhancing AAD expression, which could promote dopamine secretion to negative regulate Na+/K+-ATPase activity. (PMID:21982764)
• analysis of how the open conformation of human DOPA decarboxylase reveals the mechanism of PLP addition to Group II decarboxylases (PMID:22143761)
• Common allelic variants in the DDC gene may be involved in autism susceptibility. (PMID:22397633)
• This is the first study indicating the potential of DDC expression as a novel prognostic biomarker in patients with PCa who have undergone radical prostatectomy (PMID:22571720)
• This work is the first to shed light on the potential clinical usefulness of DDC, as an efficient tumor biomarker in gastric cancer. (PMID:23064786)
• The aim of the current study was to analyze the DDC mRNA expression in head and neck squamous cell carcinoma (HNSCC) patients. DDC mRNA levels were lower in squamous cell carcinomas of the larynx and tongue than in adjacent non-cancerous tissue specimens. (PMID:23083099)
• This study provides the first evidence for the involvement of the DDC gene in alerting attention (PMID:23276884)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ddc	ENSDARG00000016494
mus_musculus	Ddc	ENSMUSG00000020182
rattus_norvegicus	Ddc	ENSRNOG00000004327
drosophila_melanogaster	Ddc	FBGN0000422
caenorhabditis_elegans		WBGENE00000239
caenorhabditis_elegans		WBGENE00015467

Paralogs (7): GAD1 (ENSG00000128683), GAD2 (ENSG00000136750), CSAD (ENSG00000139631), HDC (ENSG00000140287), GADL1 (ENSG00000144644), SGPL1 (ENSG00000166224), PDXDC1 (ENSG00000179889)

Protein

Protein identifiers

Aromatic-L-amino-acid decarboxylase — P20711 (reviewed: P20711)

Alternative names: DOPA decarboxylase

All UniProt accessions (11): P20711, A0A087WU57, A0A087WV24, A0A0S2Z3N4, A0A3Q8A2L5, A0A3S6CJ90, A0A3S6CLD8, A0A3S6CS67, C9JMP0, F8WER1, H7BZF7

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine and L-5-hydroxytryptophan to serotonin.

Subunit / interactions. Homodimer.

Tissue specificity. High expression in kidney.

Disease relevance. Aromatic L-amino-acid decarboxylase deficiency (AADCD) [MIM:608643] An inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency. It causes developmental and psychomotor delay, poor feeding, lethargy, ptosis, intermittent hypothermia, gastrointestinal disturbances. The onset is early in infancy and inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Catecholamine biosynthesis; dopamine biosynthesis; dopamine from L-tyrosine: step 2/2.

Similarity. Belongs to the group II decarboxylase family.

Isoforms (4)

UniProt ID	Names	Canonical?
P20711-1	1	yes
P20711-2	2, alt-DDC
P20711-3	3
P20711-4	4

RefSeq proteins (7): NP_000781, NP_001076440, NP_001229815, NP_001229816, NP_001229817, NP_001229818, NP_001229819 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002129	PyrdxlP-dep_de-COase	Domain
IPR010977	Aromatic_deC	Family
IPR015421	PyrdxlP-dep_Trfase_major	Homologous_superfamily
IPR015422	PyrdxlP-dep_Trfase_small	Homologous_superfamily
IPR015424	PyrdxlP-dep_Trfase	Homologous_superfamily
IPR021115	Pyridoxal-P_BS	Binding_site

Pfam: PF00282

Enzyme classification (BRENDA):

• EC 4.1.1.28 — aromatic-L-amino-acid decarboxylase (BRENDA: 61 organisms, 177 substrates, 177 inhibitors, 94 Km, 42 kcat entries)

Substrate kinetics (BRENDA)

26 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-DOPA	0.0001–4.27	19
3,4-DIHYDROXYPHENYLALANINE	0.039–3.3	16
L-TYROSINE	0.05–1.18	8
L-TRYPTOPHAN	0.049–2.4	7
L-PHENYLALANINE	0.099–10	6
5-HYDROXYTRYPTOPHAN	0.016–0.23	4
L-3,4-DIHYDROXYPHENYLALANINE	2.2–2.9	4
L-5-HYDROXYTRYPTOPHAN	0.038–0.155	4
L-TYR	1–3.3	3
5-HYDROXY-L-TRYPTOPHAN	0.049–0.49	2
DOPAMINE	0.0008–0.0505	2
2-FLUORO-DOPA	0.95	1
5-FLUORO-DOPA	3.35	1
5-HYDROXYTRYPTAMINE	0.066	1
6-FLUORO-DOPA	0.7	1

Catalyzed reactions (Rhea), 2 shown:

• L-dopa + H(+) = dopamine + CO2 (RHEA:12272)
• 5-hydroxy-L-tryptophan + H(+) = serotonin + CO2 (RHEA:18533)

UniProt features (72 total): helix 21, sequence variant 16, strand 14, binding site 6, splice variant 4, turn 3, repeat 2, modified residue 2, sequence conflict 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
9HRH	X-RAY DIFFRACTION	1.7
8OR9	X-RAY DIFFRACTION	1.9
9GNS	X-RAY DIFFRACTION	1.93
9HRI	X-RAY DIFFRACTION	2.05
8ORA	X-RAY DIFFRACTION	2.4
3RCH	X-RAY DIFFRACTION	2.8
3RBF	X-RAY DIFFRACTION	2.9
3RBL	X-RAY DIFFRACTION	3.24

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20711-F1	96.88	0.96

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (6): 82; 148; 149; 192; 246; 300

Post-translational modifications (2): 1, 303

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-209905	Catecholamine biosynthesis
R-HSA-209931	Serotonin and melatonin biosynthesis

MSigDB gene sets: 334 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, MODULE_445, RODRIGUES_NTN1_TARGETS_DN, GOBP_DOPAMINE_METABOLIC_PROCESS, KEGG_HISTIDINE_METABOLISM, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, DIERICK_SEROTONIN_FUNCTION_GENES, JEON_SMAD6_TARGETS_DN, GOBP_INDOLE_CONTAINING_COMPOUND_METABOLIC_PROCESS, MODULE_373, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, ABBUD_LIF_SIGNALING_1_DN, SANSOM_APC_TARGETS_DN, MODULE_88

GO Biological Process (11): kidney development (GO:0001822), amino acid metabolic process (GO:0006520), catecholamine metabolic process (GO:0006584), response to toxic substance (GO:0009636), gene expression (GO:0010467), carboxylic acid metabolic process (GO:0019752), dopamine biosynthetic process (GO:0042416), serotonin biosynthetic process (GO:0042427), biogenic amine metabolic process (GO:0006576), biogenic amine biosynthetic process (GO:0042401), catecholamine biosynthetic process (GO:0042423)

GO Molecular Function (9): aromatic-L-amino-acid decarboxylase activity (GO:0004058), enzyme binding (GO:0019899), pyridoxal phosphate binding (GO:0030170), 5-hydroxy-L-tryptophan decarboxylase activity (GO:0036467), L-dopa decarboxylase activity (GO:0036468), protein binding (GO:0005515), lyase activity (GO:0016829), carbon-carbon lyase activity (GO:0016830), carboxy-lyase activity (GO:0016831)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of amine-derived hormones	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
biogenic amine metabolic process	2
aromatic-L-amino-acid decarboxylase activity	2
cellular anatomical structure	2
animal organ development	1
renal system development	1
primary metabolic process	1
catechol-containing compound metabolic process	1
response to chemical	1
macromolecule biosynthetic process	1
oxoacid metabolic process	1
dopamine metabolic process	1
catecholamine biosynthetic process	1
serotonin metabolic process	1
indole-containing compound biosynthetic process	1
phenol-containing compound biosynthetic process	1
primary amino compound biosynthetic process	1
amine metabolic process	1
amine biosynthetic process	1
catecholamine metabolic process	1
catechol-containing compound biosynthetic process	1
biogenic amine biosynthetic process	1
carboxy-lyase activity	1
protein binding	1
anion binding	1
vitamin B6 binding	1
binding	1
catalytic activity	1
lyase activity	1
carbon-carbon lyase activity	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

2634 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DDC	SLC18A2	Q05940	965
DDC	TH	P07101	944
DDC	PNPO	Q9NVS9	896
DDC	MAOB	P27338	873
DDC	MAOA	P21397	864
DDC	SLC6A3	Q01959	860
DDC	DBH	P09172	820
DDC	COMT	P21964	813
DDC	PAH	P00439	781
DDC	TOMT	Q8WZ04	772
DDC	TPH1	P17752	770
DDC	SLC6A4	P31645	751
DDC	PNMT	P11086	732
DDC	AOC1	P19801	723
DDC	QDPR	P09417	721

IntAct

8 interactions, top by confidence:

A	B	Type	Score
AR	DDC	psi-mi:“MI:0915”(physical association)	0.510
DDC	DDC	psi-mi:“MI:0407”(direct interaction)	0.440
Ar	DDC	psi-mi:“MI:0407”(direct interaction)	0.440
DDC	RELA	psi-mi:“MI:0915”(physical association)	0.370
ATF6	DDC	psi-mi:“MI:0915”(physical association)	0.370
BSG	METTL15	psi-mi:“MI:0914”(association)	0.350

BioGRID (7): DDC (Affinity Capture-MS), DDC (Affinity Capture-MS), DDC (Proximity Label-MS), DDC (Affinity Capture-MS), DDC (Proximity Label-MS), RELA (Two-hybrid), DDC (Two-hybrid)

ESM2 similar proteins: A0A2H5AIY0, A0A2H5AIY2, A0A2I6B3P0, A0AA51Z3J4, A6QM00, A8XKT0, O82415, O88533, O96567, O96569, O96571, P05031, P14173, P17770, P18486, P20228, P20711, P22781, P27718, P48320, P48321, P48861, P54768, P54769, P54770, P54771, P80041, P81893, P93082, P93083, Q05329, Q05683, Q06085, Q06086, Q06087, Q06088, Q0VCA1, Q0ZQX0, Q0ZS27, Q16S21

Diamond homologs: A0A2H5AIY0, A0A2H5AIY2, A0A2I6B3P0, A0AA51Z3J4, O82415, O88533, O96567, O96569, O96571, P05031, P14173, P16453, P17770, P18486, P19113, P20711, P22781, P23738, P27718, P34751, P48861, P54768, P54769, P54770, P54771, P80041, P81893, P93082, P93083, Q05733, Q06085, Q06086, Q06087, Q06088, Q0ZQX0, Q0ZS27, Q16S21, Q5EA83, Q6ZJK7, Q7XHL3

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
DDC	“down-regulates quantity”	L-dopa	“chemical modification”
DDC	“down-regulates quantity”	tyrosine	“chemical modification”
DDC	“up-regulates quantity”	tyramine	“chemical modification”
DDC	“down-regulates quantity”	5-hydroxy-L-tryptophan	“chemical modification”
DDC	“up-regulates quantity”	dopamine	“chemical modification”
DDC	“up-regulates quantity”	serotonin	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

668 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	47
Likely pathogenic	27
Uncertain significance	219
Likely benign	263
Benign	46

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1034300	NM_001082971.2(DDC):c.19C>T (p.Arg7Ter)	Pathogenic
1036808	NM_001082971.2(DDC):c.367G>A (p.Gly123Arg)	Pathogenic
1068763	NM_001082971.2(DDC):c.1297dup (p.Ile433fs)	Pathogenic
1069673	NC_000007.13:g.(?50563038)(50563125_?)del	Pathogenic
1075848	NM_001082971.2(DDC):c.480del (p.Thr161fs)	Pathogenic
1353224	NM_001082971.2(DDC):c.48_49delinsAG (p.Tyr16_Met17delinsTer)	Pathogenic
1355136	NM_001082971.2(DDC):c.564_568dup (p.Gln190fs)	Pathogenic
1373356	NM_001082971.2(DDC):c.82C>T (p.Gln28Ter)	Pathogenic
1374428	NM_001082971.2(DDC):c.1233del (p.Arg412fs)	Pathogenic
1385192	NM_001082971.2(DDC):c.526C>T (p.Gln176Ter)	Pathogenic
1433147	NM_001082971.2(DDC):c.568C>T (p.Gln190Ter)	Pathogenic
1683497	NM_001082971.2(DDC):c.995A>G (p.Tyr332Cys)	Pathogenic
17809	NM_001082971.2(DDC):c.304G>A (p.Gly102Ser)	Pathogenic
17810	NM_001082971.2(DDC):c.749C>T (p.Ser250Phe)	Pathogenic
17811	NM_001082971.2(DDC):c.925T>C (p.Phe309Leu)	Pathogenic
17812	NM_001082971.2(DDC):c.439A>C (p.Ser147Arg)	Pathogenic
2022937	NM_001082971.2(DDC):c.1107T>A (p.Tyr369Ter)	Pathogenic
2030127	NM_001082971.2(DDC):c.1013_1016dup (p.Asp339fs)	Pathogenic
2033490	NM_001242889.2(DDC):c.435+8518_435+8519del	Pathogenic
2044171	NM_001082971.2(DDC):c.254C>A (p.Ser85Ter)	Pathogenic
2136536	NM_001082971.2(DDC):c.1385G>C (p.Arg462Pro)	Pathogenic
2136538	NM_001082971.2(DDC):c.665T>C (p.Leu222Pro)	Pathogenic
2423396	NC_000007.13:g.(?50571671)(50571777_?)del	Pathogenic
2423397	NC_000007.13:g.(?50605538)(50611783_?)del	Pathogenic
2735023	NM_001082971.2(DDC):c.1340G>A (p.Arg447His)	Pathogenic
2739474	NM_001082971.2(DDC):c.764T>A (p.Leu255Ter)	Pathogenic
2741822	NM_001082971.2(DDC):c.801G>A (p.Trp267Ter)	Pathogenic
2836687	NM_001082971.2(DDC):c.362G>A (p.Trp121Ter)	Pathogenic
3020017	NM_001082971.2(DDC):c.867_871TGGAG[1] (p.Glu292fs)	Pathogenic
3385264	NM_001082971.2(DDC):c.208C>T (p.His70Tyr)	Pathogenic

SpliceAI

2906 predictions. Top by Δscore:

Variant	Effect	Δscore
7:50463236:C:CA	donor_gain	1.0000
7:50528135:A:AC	donor_gain	1.0000
7:50528136:C:CC	donor_gain	1.0000
7:50528180:T:TA	donor_gain	1.0000
7:50529204:TCA:T	donor_loss	1.0000
7:50529205:CA:C	donor_loss	1.0000
7:50529206:A:AC	donor_gain	1.0000
7:50529207:C:CC	donor_gain	1.0000
7:50529207:C:CG	donor_loss	1.0000
7:50529338:CTTCC:C	acceptor_gain	1.0000
7:50529341:CC:C	acceptor_gain	1.0000
7:50529342:CC:C	acceptor_gain	1.0000
7:50529343:C:T	acceptor_gain	1.0000
7:50529350:C:CT	acceptor_gain	1.0000
7:50537854:CCTTA:C	donor_loss	1.0000
7:50537855:CTTA:C	donor_loss	1.0000
7:50537856:TTA:T	donor_loss	1.0000
7:50537857:TA:T	donor_loss	1.0000
7:50537858:ACC:A	donor_loss	1.0000
7:50537858:ACCTG:A	donor_loss	1.0000
7:50537859:C:A	donor_loss	1.0000
7:50543881:TTA:T	donor_loss	1.0000
7:50543882:T:TG	donor_loss	1.0000
7:50543883:A:AC	donor_gain	1.0000
7:50543883:A:AG	donor_loss	1.0000
7:50543883:AC:A	donor_gain	1.0000
7:50543883:ACC:A	donor_gain	1.0000
7:50543883:ACCC:A	donor_gain	1.0000
7:50543884:C:CC	donor_gain	1.0000
7:50543884:CC:C	donor_gain	1.0000

AlphaMissense

3147 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:50495386:T:A	K303I	1.000
7:50495351:A:G	W315R	0.999
7:50495351:A:T	W315R	0.999
7:50495385:T:A	K303N	0.998
7:50495385:T:G	K303N	0.998
7:50495386:T:G	K303T	0.998
7:50495394:A:C	N300K	0.998
7:50495394:A:T	N300K	0.998
7:50529331:A:C	S149R	0.998
7:50529331:A:T	S149R	0.998
7:50529333:T:G	S149R	0.998
7:50529337:A:C	S147R	0.998
7:50529337:A:T	S147R	0.998
7:50529339:T:G	S147R	0.998
7:50537951:T:A	E115V	0.998
7:50540019:A:G	W71R	0.998
7:50540019:A:T	W71R	0.998
7:50470126:A:G	W363R	0.997
7:50470126:A:T	W363R	0.997
7:50470148:T:A	R355S	0.997
7:50470148:T:G	R355S	0.997
7:50495408:A:G	S296P	0.997
7:50499193:A:C	S277R	0.997
7:50499193:A:T	S277R	0.997
7:50499195:T:G	S277R	0.997
7:50499210:C:G	A272P	0.997
7:50504044:C:A	G244W	0.997
7:50537954:A:G	L114P	0.997
7:50470149:C:G	R355T	0.996
7:50495359:G:A	S312F	0.996

dbSNP variants (sampled 300 via entrez): RS1000058830 (7:50466805 C>T), RS1000079887 (7:50533843 T>C,G), RS1000120387 (7:50467300 G>C), RS1000142591 (7:50550058 G>A,C), RS1000147008 (7:50489447 T>C), RS1000164056 (7:50472499 G>T), RS1000194555 (7:50475634 G>A), RS1000196795 (7:50550249 G>T), RS1000230618 (7:50472909 G>T), RS1000231912 (7:50500508 T>C,G), RS1000245606 (7:50516724 C>A), RS1000281641 (7:50472666 C>T), RS1000347773 (7:50478046 A>T), RS1000365007 (7:50484718 C>T), RS1000399588 (7:50561417 G>A,C,T)

Disease associations

OMIM: gene MIM:107930 | disease phenotypes: MIM:608643

GenCC curated gene-disease

Disease	Classification	Inheritance
aromatic L-amino acid decarboxylase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
aromatic L-amino acid decarboxylase deficiency	Definitive	AR

Mondo (2): aromatic L-amino acid decarboxylase deficiency (MONDO:0012084), RASopathy (MONDO:0021060)

Orphanet (2): Aromatic L-amino acid decarboxylase deficiency (Orphanet:35708), RASopathy (Orphanet:536391)

HPO phenotypes

62 total (30 of 62 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000271	Abnormality of the face
HP:0000473	Torticollis
HP:0000508	Ptosis
HP:0000616	Miosis
HP:0000643	Blepharospasm
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000729	Autistic behavior
HP:0000737	Irritability
HP:0000870	Increased circulating prolactin concentration
HP:0000975	Hyperhidrosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001270	Motor delay
HP:0001315	Reduced tendon reflexes
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001742	Nasal congestion
HP:0001943	Hypoglycemia
HP:0002014	Diarrhea
HP:0002015	Dysphagia

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000410_1	Malaria	6.000000e-06
GCST000464_6	Acute lymphoblastic leukemia (childhood)	8.000000e-11
GCST001320_16	Acute lymphoblastic leukemia (childhood)	2.000000e-07
GCST001320_18	Acute lymphoblastic leukemia (childhood)	2.000000e-08
GCST001912_1	Acute lymphoblastic leukemia (childhood)	2.000000e-29
GCST002604_1	Schizophrenia (treatment resistant)	6.000000e-07
GCST002783_396	Body mass index	5.000000e-07
GCST002783_483	Body mass index	1.000000e-06
GCST005950_9	Body mass index x sex x age interaction (4df test)	2.000000e-09
GCST005951_200	Body mass index	2.000000e-08
GCST005953_3	Body mass index (age <50)	8.000000e-10
GCST007565_188	Morning person	8.000000e-21
GCST007576_343	Chronotype	8.000000e-21
GCST010988_155	Adult body size	4.000000e-08
GCST012020_571	Serum metabolite levels	2.000000e-12
GCST012021_19	Serum metabolite levels	2.000000e-12

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0008328	chronotype measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537437	Aromatic amino acid decarboxylase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1843 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs12718541	Toxicity	3	nicotine	Tobacco Use Disorder

PharmGKB variants

8 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs921451	DDC		0.00	0
rs1451371	DDC		0.00	0
rs2060761	DDC		0.00	0
rs3735273	DDC		0.00	0
rs3757472	DDC		0.00	0
rs12718541	DDC	3	2.50	1	nicotine
rs11575553	DDC		0.00	0
rs12666409	DDC		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Catecholamine turnover

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.39	Kd	40.88	nM	CHEMBL3752910
7.39	ED50	40.88	nM	CHEMBL3752910
5.82	Kd	1524	nM	CHEMBL5653589
5.82	ED50	1524	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 32 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148209: Binding affinity to human DDC incubated for 45 mins by Kinobead based pull down assay	kd	0.0409	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148209: Binding affinity to human DDC incubated for 45 mins by Kinobead based pull down assay	kd	1.5241	uM

CTD chemical–gene interactions

84 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	7
Aflatoxin B1	affects expression, decreases expression, decreases methylation	5
Cyclosporine	decreases expression, increases expression	4
Levodopa	affects cotreatment, decreases abundance, increases abundance, affects binding, increases metabolic processing (+1 more)	3
bisphenol A	affects cotreatment, increases methylation, affects expression	2
sarpogrelate	increases expression, decreases reaction	2
deguelin	decreases expression	2
pyrachlostrobin	decreases expression	2
picoxystrobin	decreases expression	2
Malathion	affects binding, increases expression	2
Sarin	affects binding, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tretinoin	decreases expression, increases expression	2
novichok	affects binding	1
securinine	decreases expression	1
benserazide, levodopa drug combination	decreases expression	1
methyleugenol	decreases expression	1
mipafox	affects binding	1
propionaldehyde	decreases expression	1
carbidopa, levodopa drug combination	decreases expression	1
tabun	affects binding	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects binding	1
VX-agent	affects binding	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
2-amino-3-methyl-9H-pyrido(2,3-b)indole	decreases activity	1
sodium arsenite	increases expression	1
3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole	decreases activity	1
3-amino-1-methyl-5H-pyrido(4,3-b)indole	decreases activity	1
periodate-oxidized adenosine	affects expression	1
phenylsaligenin cyclic phosphate	affects binding	1

ChEMBL screening assays

8 unique, capped per target: 6 functional, 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3295577	Binding	Inhibition of recombinant human DOPA decarboxylase assessed as inhibition of dopamine production after 30 mins by HPLC method	Synthesis of 5-methyl phenanthridium derivatives: a new class of human DOPA decarboxylase inhibitors. — Bioorg Med Chem Lett
CHEMBL668407	Functional	Decrease of DOPA formation effected by 30 mg/kg administered intraperitoneally in the striatum of GBL-treated rats	4-(1,2,5,6-Tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamines: a novel class of compounds with central dopamine agonist properties. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_QY30	IBMS-iPSC-029-01	Induced pluripotent stem cell	Female
CVCL_RP80	IBMS-iPSC-027-01	Induced pluripotent stem cell	Male
CVCL_UD69	IBMS-iPSC-028-01	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

18 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02926066	PHASE2	COMPLETED	A Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC - An Expansion
NCT04903288	PHASE2	ACTIVE_NOT_RECRUITING	A Study of SmartFlow Magnetic Resonance (MR) Compatible Ventricular Cannula for Administering Eladocagene Exuparvovec to Pediatric Participants
NCT02852213	PHASE1	RECRUITING	A Single-Stage, Adaptive, Open-label, Dose Escalation Safety and Efficacy Study of AADC Deficiency in Pediatric Patients
NCT06432140	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Trial to Evaluate Safety and Efficacy of a Product Named VGN-R09b in Severe AADC Deficiency
NCT01395641	PHASE1/PHASE2	COMPLETED	A Phase I/II Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC
NCT05765981	EARLY_PHASE1	RECRUITING	An Early Clinical Trial to Evaluate VGN-R09b for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency.
NCT02399761	Not specified	COMPLETED	Newborn Screening for Aromatic L-amino Acid Decarboxylase Deficiency
NCT05211609	Not specified	UNKNOWN	Prevalence of High Plasmatic 3OMethyldopa Level in a Specific Population of Patients With a Symptomatology Compatible With AADC Deficiency
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT04888936	Not specified	RECRUITING	Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
NCT05761314	Not specified	RECRUITING	Solid Tumors in RASopathies
NCT06331117	Not specified	UNKNOWN	Effect of RAS/MAPK Pathway Hyperactivation on Growth’ and Bone’ Profile of the RASopathies
NCT06355622	Not specified	UNKNOWN	Prevalence and Characterization of Pain in RASopathies
NCT06489067	Not specified	RECRUITING	Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)
NCT06776380	Not specified	RECRUITING	Pubertal Development in Patients with RASopathies
NCT07005297	Not specified	NOT_YET_RECRUITING	Clinical Genetics Branch Eligibility Screening Survey
NCT07344480	Not specified	RECRUITING	Retrospective Natural History Study of RASopathy-associated Cardiomyopathy (RAS-CM)
NCT07464821	Not specified	RECRUITING	National Multicentre Study on Lipid Profile in Noonan Syndrome and Related Disorders: Trends by Age, Gender and Genotype