PDYN

Summary

PDYN (prodynorphin, HGNC:8820) is a protein-coding gene on chromosome 20p13, encoding Proenkephalin-B (P01213). Leu-enkephalins compete with and mimic the effects of opiate drugs.

The protein encoded by this gene is a preproprotein that is proteolytically processed to form the secreted opioid peptides beta-neoendorphin, dynorphin, leu-enkephalin, rimorphin, and leumorphin. These peptides are ligands for the kappa-type of opioid receptor. Dynorphin is involved in modulating responses to several psychoactive substances, including cocaine. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 5173 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia type 23 (Strong, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 177 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 24
• Druggable target: yes
• MANE Select transcript: NM_024411

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8820
Approved symbol	PDYN
Name	prodynorphin
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	PENKB, ADCA
Ensembl gene	ENSG00000101327
Ensembl biotype	protein_coding
OMIM	131340
Entrez	5173

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000217305, ENST00000539905, ENST00000540134, ENST00000650824, ENST00000650874, ENST00000650937, ENST00000651328, ENST00000651684, ENST00000651882, ENST00000651996, ENST00000652436

RefSeq mRNA: 5 — MANE Select: NM_024411 NM_001190892, NM_001190898, NM_001190899, NM_001190900, NM_024411

CCDS: CCDS13023

Canonical transcript exons

ENST00000217305 — 4 exons

Exon	Start	End
ENSE00000655739	1982956	1983103
ENSE00001108022	1978759	1980958
ENSE00001374469	1993911	1994058
ENSE00001377162	1992584	1992643

Expression profiles

Bgee: expression breadth broad, 85 present calls, max score 93.83.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6577 / max 172.5625, expressed in 93 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186071	0.4133	68
186072	0.1632	55
186073	0.0812	42

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	93.83	gold quality
caudate nucleus	UBERON:0001873	86.95	gold quality
putamen	UBERON:0001874	82.28	gold quality
amygdala	UBERON:0001876	75.82	gold quality
right testis	UBERON:0004534	72.75	gold quality
left testis	UBERON:0004533	72.64	gold quality
Ammon’s horn	UBERON:0001954	72.54	gold quality
temporal lobe	UBERON:0001871	71.52	gold quality
hypothalamus	UBERON:0001898	71.25	gold quality
telencephalon	UBERON:0001893	71.13	gold quality
prefrontal cortex	UBERON:0000451	69.83	gold quality
testis	UBERON:0000473	69.83	gold quality
cingulate cortex	UBERON:0003027	69.71	gold quality
lateral globus pallidus	UBERON:0002476	69.65	silver quality
anterior cingulate cortex	UBERON:0009835	69.42	gold quality
entorhinal cortex	UBERON:0002728	68.87	gold quality
forebrain	UBERON:0001890	67.82	gold quality
middle frontal gyrus	UBERON:0002702	66.52	gold quality
cerebral cortex	UBERON:0000956	65.86	gold quality
Brodmann (1909) area 9	UBERON:0013540	65.81	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	64.86	gold quality
frontal cortex	UBERON:0001870	64.65	gold quality
neocortex	UBERON:0001950	64.63	gold quality
brain	UBERON:0000955	63.43	gold quality
central nervous system	UBERON:0001017	63.18	gold quality
right frontal lobe	UBERON:0002810	62.60	gold quality
postcentral gyrus	UBERON:0002581	59.92	silver quality
Brodmann (1909) area 10	UBERON:0013541	58.64	gold quality
superior frontal gyrus	UBERON:0002661	58.10	gold quality
sperm	CL:0000019	57.93	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-8894	yes	2155.80
E-HCAD-5	yes	1045.48
E-ANND-3	yes	2.94

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CREB1, DEAF1, FOS, GLI3, IRF2BPL, JUN, KCNIP3, NEUROD1, NEUROD2, NEUROD6, PTF1A, SP1

miRNA regulators (miRDB)

75 targeting PDYN, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-1179	99.71	68.70	1040
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-3202	99.66	67.70	2737

Literature-anchored findings (GeneRIF, showing 40)

• Prodynorphin mRNA reduction could modulate endocrine and autonomic mechanisms in subjects with affective disorders. (PMID:11803449)
• results suggest that allelic variation at the promoter region of the prodynorphin gene, which may result in enhanced gene transcription, may contribute to relative protection and decrease individual vulnerability to develop cocaine dependence or abuse (PMID:11992566)
• The PFYN gene polymorphism alone does not alter the risk for schizophrenia, but may contribute to the genetic susceptibility. (PMID:12207142)
• Increased preproenkephalin-B mRNA expression, with subsequent elevations in opioid peptide transmission within the direct striatal output pathways, may underlie treatment-related dyskinesia in Parkinson’s disease (PMID:14552886)
• dynorphin can signal information to the cell interior through neuropeptide translocation across the plasma membrane (PMID:15894804)
• Study provides new data regarding the potential role of the prodynorphin promoter variable nucleotide tandem repeat (VNTR) polymorphism in cocaine dependence (PMID:16184603)
• positive natural selection altered the cis-regulation of human prodynorphin, the precursor molecule for a suite of endogenous opioids and neuropeptides with critical roles in regulating perception, behavior, and memory (PMID:16274263)
• PDYN repeat polymorphism should be studied in additional opioid-dependent populations. (PMID:16314761)
• A 3- or 4-repeat allele in the PDYN gene promoter, which was shown to produce significantly higher transcription activity of the PDYN gene than a 1- or 2-repeat allele, is a genetic risk factor for development of methamphetamine dependence. (PMID:16529859)
• Alzheimer’s disease (AD) brains display robustly elevated levels of dynorphin A and no differences in dynorphin B and nociceptin compared to controls, suggesting a role for this neuropeptide in AD neuropathology. (PMID:16914231)
• Family-based analyses demonstrated associations between alcohol dependence and multiple SNPs in the promoter and 3’ end of PDYN. (PMID:16924269)
• significant difference in grouped genotype frequency between the cocaine/alcohol-codependent group and the controls in African Americans, with genotypes containing longer alleles found at higher frequency in the codependent group (PMID:17559549)
• analysis of polymorphisms of proenkephalin (PENK) and prodynorphin (PDYN) genes in relation to heroin abuse and gene expression in the human striatum and the relevance of genetic dopaminergic tone (PMID:18184800)
• functional allelic variants in the PDYN promoter might modify the risk to develop temporal lobe epilepsy in subjects with familial predisposition (PMID:18334734)
• tendency towards association with the prodynorphin low expression (L) alleles was found in the small group of Autosomal dominant lateral temporal epilepsy index cases (PMID:18355961)
• compared six single nucleotide polymorphisms of PDYN, showed that one is associated with cocaine addiction and/or cocaine/alcohol codependence vulnerability and that it is related to lower mRNA expression of the PDYN gene in the striatum (PMID:18923396)
• changes in prodynorphin gene expression and neuronal morphology in the hypothalamus of postmenopausal women; decreased dynorphin gene expression could play a role in the elevation in luteinising hormone secretion that occurs in postmenopausal women (PMID:19094085)
• Linkage peaks were typically found in regions previously identified in linkage studies and/or containing proposed candidate genes for alcoholism including AGT, OPRD1, and PDYN. (PMID:19183129)
• SNPs in PDYN are significantly associated with the risk of developing opioid dependence; however, this effect may only be seen in females. (PMID:19298317)
• This study demenerdtrated that pronounced increases of prodynorphin mRNA expression in the dentate gyrus of patients with temporal lobe epilepsy in comparison to controls. (PMID:19437412)
• Thus, our results suggest a role of PDYN gene variations in determining memory function also in elderly humans. (PMID:19468819)
• Dynorphin immunoreactive fibers contact GnRH neurons in the human hypothalamus. (PMID:19474285)
• These data do not provide evidence for an association of the PDYN promoter polymorphism and Atopic Dermatitis in general, thus, a strong influence of the PDYN gene and its promoter polymorphism on the development of atopic dermatitis is unlikely. (PMID:19486061)
• PDYN is present within alveolar macrophages and cancerous cells of lung cancer patients. (PMID:20376782)
• These results further our understanding of the complex transcriptional regulation of the PDYN gene promoter. (PMID:20731629)
• Tissue-specific DNA methylation of the human prodynorphin gene in post-mortem brain tissues and PBMCs (PMID:20808262)
• PDYN mutations are identified in a small subset of ataxia families, indicating that SCA23 is an infrequent SCA type ( approximately 0.5%) in the Netherlands and suggesting further genetic SCA heterogeneity. (PMID:21035104)
• Prodynorphin expression in the dorsolateral prefrontal cortex may be related to alcoholism, while in the hippocampus it may depend on the genotype. (PMID:21338584)
• This study support the important role of PDYN polymorphism in heroin dependence. (PMID:21382455)
• Three PDYN CpG-SNPs associated with alcoholism were found to be differently methylated in the human brain. (PMID:21521424)
• The overall correlation between membrane perturbation and neurotoxic response suggests that pathogenic Dyn A actions may be mediated through transient pore formation in lipid domains of the plasma membrane. (PMID:21712028)
• allele. These results indicate that variation in the PDYN gene is associated with a dimensional trait or intermediate phenotype that reflects a preference for heavy drinking and engaging in related risky behaviors. (PMID:21736916)
• findings clearly indicate a very low frequency of spinocerebellar ataxia type 23 (SCA23) caused by PDYN mutations in Germany (PMID:22243190)
• These data show that polymorphisms in PDYN are associated with opioid addiction in European Americans and provide further evidence that these risk variants may be more relevant in females. (PMID:22443215)
• trauma may reveal a lateralization in the mechanism mediating the response of Dyn A-expressing neuronal networks in the brain (PMID:22468884)
• Pairwise tag single nucleotide polymorphisms (SNPs) in DREAM, PDYN and OPRK1 were genotyped in a United Kingdom population-based discovery cohort in whom pain was assessed. (PMID:22730276)
• Human volunteers bearing the T allele of PDYN (prodynorphin) show reduced fear extinction. (PMID:22764240)
• Cytosine methylation at CpG sites affects the conformational flexibility of short ssDNA molecules was shown by using PDYN (prodynorphin) fragments as model molecules. (PMID:22768096)
• To investigate the frequency of SCA23 among the Chinese Han population, we performed polymerase chain reaction (PCR) and DNA direct sequencing of the PDYN gene in 305 unrelated ataxia patients (PMID:22985506)
• The sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol-dependent subjects. (PMID:23101464)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdyn	ENSDARG00000087798
mus_musculus	Pdyn	ENSMUSG00000027400
rattus_norvegicus	Pdyn	ENSRNOG00000026036

Paralogs (2): PNOC (ENSG00000168081), PENK (ENSG00000181195)

Protein

Protein identifiers

Proenkephalin-B — P01213 (reviewed: P01213)

Alternative names: Beta-neoendorphin-dynorphin, Preprodynorphin

All UniProt accessions (9): P01213, A0A494C0B1, A0A494C0B3, A0A494C0X3, A0A494C0Y8, A0A494C197, A0A494C1E3, A0A494C1J4, A0A494C1U2

UniProt curated annotations — full annotation on UniProt →

Function. Leu-enkephalins compete with and mimic the effects of opiate drugs. They play a role in a number of physiologic functions, including pain perception and responses to stress. Dynorphin peptides differentially regulate the kappa opioid receptor. Dynorphin A(1-13) has a typical opioid activity, it is 700 times more potent than Leu-enkephalin. Leumorphin has a typical opioid activity and may have anti-apoptotic effect.

Subcellular location. Secreted.

Post-translational modifications. The N-terminal domain contains 6 conserved cysteines thought to be involved in disulfide bonding and/or processing.

Disease relevance. Spinocerebellar ataxia 23 (SCA23) [MIM:610245] Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA23 is an adult-onset autosomal dominant form characterized by slowly progressive gait and limb ataxia, with variable additional features, including peripheral neuropathy and dysarthria. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the opioid neuropeptide precursor family.

RefSeq proteins (5): NP_001177821, NP_001177827, NP_001177828, NP_001177829, NP_077722* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000750	Proenkphlin_B	Family
IPR006024	Opioid_neupept	Family

Pfam: PF01160

UniProt features (24 total): peptide 11, sequence variant 9, propeptide 2, signal peptide 1, strand 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
8VJU	X-RAY DIFFRACTION	1.99
8VJV	X-RAY DIFFRACTION	2.12
9L60	ELECTRON MICROSCOPY	2.9
9CCE	X-RAY DIFFRACTION	3.15
8F7W	ELECTRON MICROSCOPY	3.19
7Y1F	ELECTRON MICROSCOPY	3.3
9CCF	X-RAY DIFFRACTION	4
2N2F	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01213-F1	58.95	0.01

Antibody-complex structures (SAbDab): 2 — 7Y1F, 8F7W

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-111885	Opioid Signalling
R-HSA-202040	G-protein activation
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-418594	G alpha (i) signalling events

MSigDB gene sets: 156 (showing top): GOCC_SECRETORY_GRANULE, LFA1_Q6, MODULE_64, GOBP_CELL_CELL_SIGNALING, BROWNE_HCMV_INFECTION_24HR_UP, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, MODULE_289, REACTOME_G_PROTEIN_ACTIVATION, MODULE_99, GOBP_SYNAPTIC_SIGNALING, NKX22_01, TATA_C, AACTTT_UNKNOWN, GOBP_SENSORY_PERCEPTION, BROWNE_HCMV_INFECTION_6HR_UP

GO Biological Process (3): neuropeptide signaling pathway (GO:0007218), chemical synaptic transmission (GO:0007268), sensory perception (GO:0007600)

GO Molecular Function (3): opioid peptide activity (GO:0001515), opioid receptor binding (GO:0031628), protein binding (GO:0005515)

GO Cellular Component (8): extracellular region (GO:0005576), plasma membrane (GO:0005886), dendrite (GO:0030425), neuronal cell body (GO:0043025), axon terminus (GO:0043679), hippocampal mossy fiber to CA3 synapse (GO:0098686), neuronal dense core vesicle (GO:0098992), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
G alpha (i) signalling events	1
Opioid Signalling	1
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	1
anterograde trans-synaptic signaling	1
nervous system process	1
receptor ligand activity	1
G protein-coupled receptor binding	1
binding	1
cellular anatomical structure	1
membrane	1
cell periphery	1
neuron projection	1
dendritic tree	1
somatodendritic compartment	1
cell body	1
neuron projection terminus	1
presynapse	1
distal axon	1
thorny excrescence	1
neuron to neuron synapse	1
hippocampal mossy fiber expansion	1
dense core granule	1
cell junction	1

Protein interactions and networks

STRING

2023 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDYN	PNOC	Q13519	964
PDYN	POMC	P01189	949
PDYN	TAC1	P20366	925
PDYN	NTS	P30990	906
PDYN	TAC3	Q9UHF0	880
PDYN	OPRM1	P35372	875
PDYN	NPY	P01303	862
PDYN	TRIM13	O60858	859
PDYN	KISS1	Q15726	841
PDYN	CRH	P06850	834
PDYN	GAL	P22466	822
PDYN	SST	P01166	819
PDYN	KNG1	P01042	802
PDYN	OPRD1	P41143	801
PDYN	OXT	P01178	796

IntAct

7 interactions, top by confidence:

A	B	Type	Score
LCN1	PDYN	psi-mi:“MI:0915”(physical association)	0.590
PDYN	ACAD11	psi-mi:“MI:0914”(association)	0.530
PDYN	TIMM8A	psi-mi:“MI:0914”(association)	0.350
PENK	PDYN	psi-mi:“MI:0914”(association)	0.350
PDYN	GAPDHS	psi-mi:“MI:0914”(association)	0.350

BioGRID (22): TIMM13 (Affinity Capture-MS), ACAD11 (Affinity Capture-MS), TIMM8B (Affinity Capture-MS), S100A10 (Affinity Capture-MS), GNPTG (Affinity Capture-MS), GNPTAB (Affinity Capture-MS), PDYN (Affinity Capture-MS), PDYN (Affinity Capture-MS), PDYN (Affinity Capture-MS), ACAD11 (Affinity Capture-MS), PDYN (Affinity Capture-MS), TIMM8B (Affinity Capture-MS), TIMM13 (Affinity Capture-MS), ACAD11 (Affinity Capture-MS), TIMM13 (Affinity Capture-MS)

ESM2 similar proteins: A8CL69, B2KKR4, B2ZB95, E1ZXU8, E1ZZF9, E2A1R1, E2AFK9, E2AYH6, O02036, O35417, P01213, P01360, P01361, P05305, P06300, P0C0P5, P13206, P14200, P17640, P20382, P32648, P43443, P48144, P56942, P56943, P61364, P69155, P69156, P69157, Q16N80, Q26377, Q5H8A1, Q5W1L4, Q5W1L5, Q5XXR2, Q6ZXC3, Q7PTL2, Q810H5, Q8CH01, Q8JIM3

Diamond homologs: O35417, P01211, P01213, P01214, P04094, P06300, Q60478, Q95104

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
KCNIP3	“down-regulates quantity by repression”	PDYN	“transcriptional regulation”
IRF2BPL	“down-regulates quantity by repression”	PDYN	“transcriptional regulation”
PDYN	“up-regulates activity”	OPRK1	binding
PDYN	“up-regulates activity”	OPRM1	“chemical activation”
PDYN	“up-regulates activity”	OPRD1	“chemical activation”
PDYN	“up-regulates activity”	OPRK1	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	116
Likely benign	26
Benign	17

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
18459	NM_024411.5(PDYN):c.643C>T (p.Arg215Cys)	Pathogenic
18461	NM_024411.5(PDYN):c.634C>T (p.Arg212Trp)	Likely pathogenic

SpliceAI

360 predictions. Top by Δscore:

Variant	Effect	Δscore
20:1992577:AACTC:A	donor_loss	0.9900
20:1992578:ACT:A	donor_loss	0.9900
20:1992579:CT:C	donor_loss	0.9900
20:1992580:TCA:T	donor_loss	0.9900
20:1992581:CAC:C	donor_loss	0.9900
20:1992582:A:AC	donor_gain	0.9900
20:1992583:C:CC	donor_gain	0.9900
20:1992583:C:G	donor_loss	0.9900
20:1992583:CCGG:C	donor_gain	0.9900
20:1992640:TGAC:T	acceptor_gain	0.9800
20:1992641:GACC:G	acceptor_loss	0.9800
20:1992644:C:CA	acceptor_loss	0.9800
20:1992645:T:C	acceptor_loss	0.9800
20:1992575:ATAAC:A	donor_loss	0.9700
20:1992576:TAACT:T	donor_loss	0.9700
20:1992644:C:CC	acceptor_gain	0.9700
20:1993686:CCA:C	donor_gain	0.9700
20:1993685:ACCAC:A	donor_gain	0.9500
20:1993686:CCACC:C	donor_gain	0.9500
20:1982981:T:TA	donor_gain	0.9400
20:1980954:CAAAT:C	acceptor_gain	0.9300
20:1992582:AC:A	donor_gain	0.9300
20:1992583:CC:C	donor_gain	0.9300
20:1993681:GCTTA:G	donor_loss	0.9300
20:1993682:CTTAC:C	donor_loss	0.9300
20:1993683:TTACC:T	donor_loss	0.9300
20:1993686:C:A	donor_loss	0.9300
20:1980959:C:CC	acceptor_gain	0.9200
20:1982943:G:A	donor_gain	0.9200
20:1982947:GAAAC:G	donor_loss	0.9200

AlphaMissense

1655 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:1980473:T:A	K205N	0.997
20:1980473:T:G	K205N	0.997
20:1980402:A:C	F229C	0.996
20:1980458:G:C	F210L	0.996
20:1980458:G:T	F210L	0.996
20:1980459:A:C	F210C	0.996
20:1980459:A:G	F210S	0.996
20:1980460:A:G	F210L	0.996
20:1980474:T:A	K205I	0.996
20:1980554:A:C	F178L	0.995
20:1980554:A:T	F178L	0.995
20:1980556:A:G	F178L	0.995
20:1980386:G:C	F234L	0.994
20:1980386:G:T	F234L	0.994
20:1980388:A:G	F234L	0.994
20:1980401:A:C	F229L	0.993
20:1980401:A:T	F229L	0.993
20:1980403:A:G	F229L	0.993
20:1980465:C:T	G208E	0.993
20:1980472:G:T	R206S	0.993
20:1980416:C:A	K224N	0.992
20:1980416:C:G	K224N	0.992
20:1980555:A:C	F178C	0.992
20:1980402:A:G	F229S	0.991
20:1980399:A:T	L230H	0.990
20:1980451:G:T	R213S	0.990
20:1980474:T:G	K205T	0.990
20:1980475:T:C	K205E	0.990
20:1980555:A:G	F178S	0.990
20:1980415:G:T	R225S	0.989

dbSNP variants (sampled 300 via entrez): RS1000349035 (20:1981191 G>A), RS1000381876 (20:1985324 A>G), RS1000476487 (20:1985083 A>G), RS1000660959 (20:1978775 A>G), RS1000704451 (20:1992357 C>A,T), RS1000720167 (20:1984210 C>A,T), RS1000727222 (20:1980181 G>A), RS1000881401 (20:1989506 C>A), RS1000927109 (20:1979169 C>A), RS1001026207 (20:1994759 G>A,C), RS1001186210 (20:1989737 T>C), RS1001329509 (20:1981360 G>A), RS1001351016 (20:1982246 G>A), RS1001388527 (20:1986515 A>T), RS1001481542 (20:1986253 A>C)

Disease associations

OMIM: gene MIM:131340 | disease phenotypes: MIM:610245

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia type 23	Strong	Autosomal dominant

Mondo (1): spinocerebellar ataxia type 23 (MONDO:0012449)

Orphanet (1): Spinocerebellar ataxia type 23 (Orphanet:101108)

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000514	Slow saccadic eye movements
HP:0000641	Dysmetric saccades
HP:0001260	Dysarthria
HP:0001271	Polyneuropathy
HP:0001272	Cerebellar atrophy
HP:0001274	Agenesis of corpus callosum
HP:0001310	Dysmetria
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002073	Progressive cerebellar ataxia
HP:0002166	Impaired vibration sensation in the lower limbs
HP:0002529	Neuronal loss in central nervous system
HP:0003487	Babinski sign
HP:0003584	Late onset
HP:0003596	Middle age onset
HP:0003677	Slowly progressive
HP:0006858	Impaired distal proprioception
HP:0006886	Impaired distal vibration sensation
HP:0007141	Sensorimotor neuropathy
HP:0007305	CNS demyelination
HP:0010831	Impaired proprioception

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000943_7	Aortic root size	3.000000e-08
GCST001491_5	Immune response to smallpox vaccine (IL-6)	7.000000e-07
GCST002441_7	Immune response to measles-mumps-rubella vaccine	3.000000e-07
GCST005991_48	Platelet count	4.000000e-25
GCST009391_1088	Metabolite levels	5.000000e-06
GCST009391_1325	Metabolite levels	4.000000e-06
GCST009391_1361	Metabolite levels	9.000000e-07
GCST009391_1753	Metabolite levels	9.000000e-06
GCST009391_2125	Metabolite levels	8.000000e-06

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004309	platelet count
EFO:0010543	uridine diphosphate galactose measurement
EFO:0010544	uridine diphosphate glucose measurement
EFO:0010372	phosphatidylcholine 32:0 measurement
EFO:0010366	lysophosphatidylethanolamine 16:0 measurement
EFO:0010369	lysophosphatidylethanolamine 18:2 measurement
EFO:0010382	phosphatidylcholine 36:4 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537201	Spinocerebellar ataxia 23 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2227 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1022563	Toxicity	3	opioids	Opioid-Related Disorders
rs1997794	Toxicity	3	opioids	Opioid-Related Disorders
rs910080	Toxicity	3	opioids	Opioid-Related Disorders

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1997794	PDYN	3	1.75	1	opioids
rs2235749	PDYN		0.00	0
rs910080	PDYN	3	0.75	1	opioids
rs2235751	PDYN		0.00	0
rs7272891	PDYN		0.00	0

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.15	Kd	7.1	nM	ENKEPHALIN

PubChem BioAssay actives

1 with measured affinity, of 1 total; 1 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
(2S)-2-[[(2S)-2-[[2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoic acid	101199: Dissociation constant when the monoclonal antibody 3-E7 bound tightly to [Leu]enkephalin	kd	0.0071	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cocaine	increases expression, affects response to substance, decreases response to substance, increases response to substance	6
Valproic Acid	affects cotreatment, increases expression, affects expression	6
trichostatin A	affects cotreatment, increases expression	3
entinostat	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Ethanol	decreases expression, decreases reaction, affects response to substance	2
Benzo(a)pyrene	affects methylation, increases expression	2
lasiocarpine	increases expression	1
sodium arsenite	affects methylation	1
4-hydroxy-2-nonenal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	decreases reaction, increases expression, increases response to substance	1
Decitabine	affects expression	1
Fomepizole	decreases expression, decreases reaction	1
Acetaminophen	decreases expression	1
Amiodarone	increases expression	1
Cisplatin	affects expression	1
Heroin	decreases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	decreases expression	1
Methamphetamine	increases response to substance	1
Scorpion Venoms	increases hydrolysis	1
Thimerosal	decreases reaction, increases expression, increases response to substance	1
Aflatoxin B1	decreases methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL706591	Binding	Dissociation constant when the monoclonal antibody 3-E7 bound tightly to [Leu]enkephalin	Investigations of azapeptides as mimetics of Leu-enkephalin. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford