PNKD

Summary

PNKD (PNKD metallo-beta-lactamase domain containing, HGNC:9153) is a protein-coding gene on chromosome 2q35, encoding Probable thioesterase PNKD (Q8N490). Probable thioesterase that may play a role in cellular detoxification processes; it likely acts on a yet-unknown alpha-hydroxythioester substrate.

This gene is thought to play a role in the regulation of myofibrillogenesis. Mutations in this gene have been associated with the movement disorder paroxysmal non-kinesigenic dyskinesia. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 25953 — RefSeq curated summary.

At a glance

• Gene–disease (curated): paroxysmal nonkinesigenic dyskinesia 1 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 30
• Clinical variants (ClinVar): 237 total — 2 likely-pathogenic
• Phenotypes (HPO): 24
• MANE Select transcript: NM_015488

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9153
Approved symbol	PNKD
Name	PNKD metallo-beta-lactamase domain containing
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	DYT8, PDC, DKFZp564N1362, FPD1, MR-1, BRP17, FKSG19, TAHCCP2, KIAA1184, KIPP1184, MGC31943, PKND1, MR-1S
Ensembl gene	ENSG00000127838
Ensembl biotype	protein_coding
OMIM	609023
Entrez	25953

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 13 protein_coding, 6 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000248451, ENST00000258362, ENST00000273077, ENST00000436005, ENST00000469689, ENST00000472650, ENST00000494954, ENST00000684905, ENST00000685415, ENST00000687736, ENST00000688179, ENST00000689098, ENST00000689693, ENST00000689816, ENST00000690891, ENST00000691220, ENST00000691799, ENST00000692260, ENST00000692295, ENST00000693423, ENST00000693556, ENST00000901529, ENST00000901530, ENST00000955416

RefSeq mRNA: 3 — MANE Select: NM_015488 NM_001077399, NM_015488, NM_022572

CCDS: CCDS2411, CCDS2413, CCDS42816

Canonical transcript exons

ENST00000273077 — 10 exons

Exon	Start	End
ENSE00000354075	218341534	218341626
ENSE00000876130	218340029	218340141
ENSE00000876131	218339783	218339898
ENSE00000876134	218271381	218271549
ENSE00001147205	218340728	218340786
ENSE00001405050	218343500	218343586
ENSE00001407859	218341981	218342144
ENSE00001423101	218344455	218344570
ENSE00001883338	218270519	218270602
ENSE00001929404	218344808	218346793

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 98.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.9122 / max 422.8595, expressed in 1827 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25301	22.0083	1807
25308	13.4892	1307
25307	6.3407	1472
25306	2.7529	1204
25310	0.6283	363
25305	0.4563	148
25309	0.2366	112

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
metanephros cortex	UBERON:0010533	98.01	gold quality
right lobe of liver	UBERON:0001114	97.78	gold quality
right uterine tube	UBERON:0001302	97.78	gold quality
mucosa of transverse colon	UBERON:0004991	97.77	gold quality
right lobe of thyroid gland	UBERON:0001119	97.69	gold quality
left lobe of thyroid gland	UBERON:0001120	97.66	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.57	gold quality
right frontal lobe	UBERON:0002810	97.45	gold quality
thyroid gland	UBERON:0002046	97.32	gold quality
prefrontal cortex	UBERON:0000451	97.30	gold quality
anterior cingulate cortex	UBERON:0009835	97.27	gold quality
apex of heart	UBERON:0002098	97.18	gold quality
body of stomach	UBERON:0001161	97.03	gold quality
putamen	UBERON:0001874	97.01	gold quality
right adrenal gland	UBERON:0001233	96.83	gold quality
right adrenal gland cortex	UBERON:0035827	96.75	gold quality
left adrenal gland cortex	UBERON:0035825	96.71	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.70	gold quality
nucleus accumbens	UBERON:0001882	96.69	gold quality
left adrenal gland	UBERON:0001234	96.61	gold quality
amygdala	UBERON:0001876	96.60	gold quality
caudate nucleus	UBERON:0001873	96.49	gold quality
right atrium auricular region	UBERON:0006631	96.46	gold quality
transverse colon	UBERON:0001157	96.44	gold quality
hypothalamus	UBERON:0001898	96.41	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.41	gold quality
adrenal cortex	UBERON:0001235	96.27	gold quality
cardiac atrium	UBERON:0002081	96.19	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.15	gold quality
adult mammalian kidney	UBERON:0000082	96.05	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	19.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting PNKD, 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-10401-5P	99.99	65.79	948
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-6861-3P	99.60	68.46	444
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-3622A-5P	97.43	67.11	356

Literature-anchored findings (GeneRIF, showing 20)

• MR-1 is a novel myofibrillogenesis regulator in human muscle (PMID:15188056)
• Different missense mutations in exon 1 of MR1 that cosegregate with PNKD were identified in each multiplex family. These single-nucleotide mutations predicted substitution of valine for alanine in residue 7 in one family and residue 9 in the other. (PMID:15824259)
• autosomal dominant paroxysmal nonkinesigenic dyskinesia seems to be a homogenous disorder, for which the MR-1 gene is the major disease gene. (PMID:16632198)
• The Serbian family further demonstrates that recurrent MR-1 mutations are associated with paroxysmal nonkinesigenic dyskinesia. (PMID:16972263)
• Following down-regulation of MR-1, the phosphorylations of MLC2, focal adhesion kinase (FAK), and Akt were dramatically decreased (PMID:18948272)
• Our family was 1 of 8 families originally reported in which a mutation in the myofibrillogenesis regulator 1 (MR-1) gene caused the paroxysmal non-kinesigenic dyskinesia phenotype (PMID:18948699)
• The pnkd mutation alters such a response, suggesting that a less flexible AC region may be more effective in coupling Ca(2+) binding to channel opening. (PMID:20620873)
• Mutations in PNKD causing paroxysmal dyskinesia alters protein cleavage and stability. (PMID:21487022)
• In this report we present two families with paroxysmal non-kinesigenic dyskinesia of Southern European origin carrying a PNKD protein recurrent mutation. (PMID:21962874)
• MR-1S is highly expressed in ovarian cancer cells and tissues. (PMID:22780969)
• A Taiwanese family with paroxysmal nonkinesigenic dyskinesia has a heterozygous c.20 C>T (p.Ala7Val) mutation which was clearly segregated in the five affected patients. (PMID:22967746)
• MR-1 was up-regulated in gastric cancer tissues. High expression of MR-1 in gastric cancer was significantly correlated with clinical stage. Postoperative survival of the MR-1 positive group tended to be poorer than that of the MR-1 negative group. (PMID:23082061)
• MR-1 overexpression was tightly associated with more aggressive tumor behavior and a poor prognosis in pancreatic ductal adenocarcinoma. (PMID:23696030)
• MR-1 functions as a tumor promoter in MCF7 cells by activating the MEK/ERK signaling (PMID:25066297)
• This study present the pedigree is the first PNKD family from Chinese Mainland, which is also the largest PNKD family among those reported across the globe. It included 5 generations and 26 patients. (PMID:25107857)
• study highlights the frequency, novel mutations and clinical and molecular spectrum of PRRT2, SLC2A1 and PNKD mutations as well as the phenotype-genotype overlap among these paroxysmal movement disorders. (PMID:26598494)
• The combined analysis identified a new risk association for colorectal cancer (CRC) at 2q35 marked by rs992157 which is intronic to PNKD and TMBIM1.Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r(2) = 0.90, D’ = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). (PMID:27005424)
• The short isoform of the myofibrillogenesis regulator 1 (MR-1S) as a new COX assembly factor, which works with the highly conserved PET100 and PET117 chaperones to assist COX biogenesis in higher eukaryotes. (PMID:28199844)
• A rare heterozygous nonsense mutation (C to T transition) was identified in a Tourette Disorder multiplex family by whole exome sequencing. Tourette or Tic Disorder-affected family members shared a heterozygous nonsense mutation (chr2: 219204814 C/T), which is not present in the unaffected individuals and absent in the background sample (PMID:28894297)
• Myofibrillogenesis Regulator-1 Regulates the Ubiquitin Lysosomal Pathway of Notch3 Intracellular Domain Through E3 Ubiquitin-Protein Ligase Itchy Homolog in the Metastasis of Non-Small Cell Lung Cancer. (PMID:38342606)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pnkd	ENSDARG00000071032
mus_musculus	Pnkd	ENSMUSG00000026179
rattus_norvegicus	Pnkd	ENSRNOG00000014806
drosophila_melanogaster	tzn	FBGN0037024
caenorhabditis_elegans		WBGENE00012459

Paralogs (4): HAGH (ENSG00000063854), HAGHL (ENSG00000103253), ETHE1 (ENSG00000105755), MBLAC2 (ENSG00000176055)

Protein

Protein identifiers

Probable thioesterase PNKD — Q8N490 (reviewed: Q8N490)

Alternative names: Myofibrillogenesis regulator 1, Paroxysmal nonkinesiogenic dyskinesia protein, Trans-activated by hepatitis C virus core protein 2

All UniProt accessions (10): Q8N490, A0A8I5KSD7, A0A8I5KU32, A0A8I5KV27, A0A8I5KVK5, A0A8I5KVS5, A0A8I5KXK0, A0A8I5KXZ5, A0A8I5QKK6, A0A8J8ZTU4

UniProt curated annotations — full annotation on UniProt →

Function. Probable thioesterase that may play a role in cellular detoxification processes; it likely acts on a yet-unknown alpha-hydroxythioester substrate. In vitro, it is able to catalyze the hydrolysis of S-D-lactoyl-glutathione to form glutathione and D-lactic acid at very low rate, though this reaction is not physiologically relevant in vivo.

Subunit / interactions. Isoform 2 interacts with the sarcomeric proteins, MRLC2, MYOM1 and ENO3.

Subcellular location. Cell membrane. Mitochondrion Cytoplasm. Mitochondrion Mitochondrion. Golgi apparatus. Endoplasmic reticulum.

Tissue specificity. Isoform 1 is only expressed in the brain. Isoform 2 is ubiquitously detected with highest expression in skeletal muscle and detected in myocardial myofibrils.

Post-translational modifications. Undergoes cleavage at the N-terminus.

Disease relevance. Paroxysmal non-kinesigenic dyskinesia 1 (PNKD1) [MIM:118800] An autosomal dominant movement disorder characterized by attacks of dystonia, chorea, and athetosis. The attacks of involuntary movements are brought on by stress, alcohol, fatigue or caffeine, and generally last between a few seconds and four hours or longer. The attacks may begin in one limb and spread throughout the body, including the face. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 2 Zn(2+) ions per subunit.

Induction. By Hepatitis C virus core protein.

Similarity. Belongs to the metallo-beta-lactamase superfamily. Glyoxalase II family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8N490-1	1, MR-1L	yes
Q8N490-2	2, MR-1S
Q8N490-3	3, MR-1M
Q8N490-4	4

RefSeq proteins (3): NP_001070867, NP_056303, NP_072094 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001279	Metallo-B-lactamas	Domain
IPR017782	Hydroxyacylglutathione_Hdrlase	Family
IPR032282	HAGH_C	Domain
IPR035680	Clx_II_MBL	Domain
IPR036866	RibonucZ/Hydroxyglut_hydro	Homologous_superfamily

Pfam: PF00753, PF16123

Catalyzed reactions (Rhea), 1 shown:

• a thioester + H2O = a thiol + a carboxylate + H(+) (RHEA:82919)

UniProt features (24 total): binding site 8, splice variant 5, sequence variant 4, sequence conflict 4, chain 1, region of interest 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N490-F1	83.69	0.70

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 (8): 172; 174; 176; 177; 229; 253; 253; 291

Mutagenesis-validated functional residues (1):

Position	Phenotype
15	the mutant is not cleaved at the n-terminus. results in increased protein degradation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9864848	Complex IV assembly

MSigDB gene sets: 362 (showing top): FXR_IR1_Q6, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, CREL_01, SHEPARD_BMYB_MORPHOLINO_UP, PAX4_01, GAANYNYGACNY_UNKNOWN, GOBP_ALDEHYDE_CATABOLIC_PROCESS, GOBP_PHOTOTRANSDUCTION, GOBP_NEUROTRANSMITTER_TRANSPORT, AACYNNNNTTCCS_UNKNOWN, TGACCTY_ERR1_Q2, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, CHX10_01, GGGTGGRR_PAX4_03, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (5): obsolete methylglyoxal catabolic process to pyruvate via (R)-S-lactoyl-glutathione (GO:0019243), regulation of synaptic transmission, dopaminergic (GO:0032225), regulation of dopamine metabolic process (GO:0042053), negative regulation of neurotransmitter secretion (GO:0046929), neuromuscular process controlling posture (GO:0050884)

GO Molecular Function (4): hydroxyacylglutathione hydrolase activity (GO:0004416), metal ion binding (GO:0046872), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (7): mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020), presynaptic cytosol (GO:0099523), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
intracellular membrane-bounded organelle	3
endomembrane system	2
cellular anatomical structure	2
synaptic transmission, dopaminergic	1
modulation of chemical synaptic transmission	1
regulation of catecholamine metabolic process	1
dopamine metabolic process	1
neurotransmitter secretion	1
regulation of neurotransmitter secretion	1
negative regulation of neurotransmitter transport	1
negative regulation of secretion by cell	1
musculoskeletal movement	1
neuromuscular process	1
thiolester hydrolase activity	1
cation binding	1
binding	1
catalytic activity	1
membrane	1
cell periphery	1
cytosol	1
presynapse	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1584 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PNKD	PRRT2	Q7Z6L0	963
PNKD	PET117	Q6UWS5	913
PNKD	PET100	P0DJ07	902
PNKD	ASIC4	Q96FT7	890
PNKD	THAP1	Q9NVV9	598
PNKD	SLC4A3	P48751	598
PNKD	SGCE	O43556	592
PNKD	GAD1	Q99259	584
PNKD	GCH1	P30793	521
PNKD	TOR1A	O14656	506
PNKD	CIZ1	Q9ULV3	477
PNKD	ANO3	Q9BYT9	475
PNKD	ATP1A3	P13637	462
PNKD	TMEM177	Q53S58	448
PNKD	PRKRA	O75569	447

IntAct

53 interactions, top by confidence:

A	B	Type	Score
DCAF7	DIAPH1	psi-mi:“MI:0914”(association)	0.730
KLHL22	METTL15	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
PNKD	MAGEA11	psi-mi:“MI:0915”(physical association)	0.560
PNKD	KCTD9	psi-mi:“MI:0915”(physical association)	0.560
MAGEA11	PNKD	psi-mi:“MI:0915”(physical association)	0.560
KCTD9	PNKD	psi-mi:“MI:0915”(physical association)	0.560
MAPK3	PNKD	psi-mi:“MI:0915”(physical association)	0.560
MAPK3	PNKD	psi-mi:“MI:0403”(colocalization)	0.560
PNKD	MAPK3	psi-mi:“MI:0915”(physical association)	0.560
MAGEA11	PNKD	psi-mi:“MI:0915”(physical association)	0.550
PBXIP1	KCNN4	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530
ACADM	PNKD	psi-mi:“MI:0915”(physical association)	0.400
		psi-mi:“MI:0914”(association)	0.350
	PGRMC1	psi-mi:“MI:0914”(association)	0.350
MAD2L2		psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
FARP2	VAV1	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350

BioGRID (224): PNKD (Two-hybrid), KCTD9 (Two-hybrid), PNKD (Affinity Capture-MS), BTAF1 (Affinity Capture-MS), RTFDC1 (Affinity Capture-MS), EIF2B5 (Affinity Capture-MS), EIF4G3 (Affinity Capture-MS), SETX (Affinity Capture-MS), TBC1D15 (Affinity Capture-MS), TFIP11 (Affinity Capture-MS), IPO8 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS), CAMK1 (Affinity Capture-MS), IPO7 (Affinity Capture-MS), HEATR3 (Affinity Capture-MS)

ESM2 similar proteins: A0A8C2MDK8, A0A8I6GM68, A6H751, A7YY46, A8MX76, D3YXS5, D3ZBP4, D3ZEY4, E7F9T0, E9QAM5, F1MH07, F1QCV2, F8WLE0, P16452, P23249, P48760, P49222, P52824, Q2NKY8, Q2QWU2, Q3SYT1, Q3ZBE0, Q4R380, Q50L43, Q5BJS0, Q5NCQ5, Q5R607, Q5RKI3, Q5ZI74, Q69ZP3, Q6P5E8, Q6ZSI9, Q7L2E3, Q8BX80, Q8N490, Q8NFD2, Q8NFI3, Q8TDZ2, Q8TE96, Q8VDP3

Diamond homologs: A0A067XMV3, A0A1L9WLF1, A0A2I1C3U0, A0A411PQM3, A0A4P8DJU1, A0A5B8YUX5, A0A7R7ZLL0, A1D8J2, A1WXD9, A2QX23, A4YKS8, A5IBE7, A8AKR2, B0U365, B2I5S5, C5FM60, D4AWH0, D4CZZ5, D7PHZ8, E1ACR1, E4V2N5, F2PWS8, F2S702, F2T0M3, G3KLH5, M1WCF7, M3ANL0, O94250, P0CU68, Q07VA9, Q0CCY4, Q0V9A9, Q13F06, Q1LZ83, Q2J429, Q3SVQ1, Q4W945, Q4WA58, Q4WQZ6, Q53H82

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	120
Likely benign	47
Benign	21

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
432158	NM_015488.5(PNKD):c.293G>C (p.Arg98Pro)	Likely pathogenic
982213	NM_022152.6(TMBIM1):c.827G>A (p.Arg276Gln)	Likely pathogenic

SpliceAI

3874 predictions. Top by Δscore:

Variant	Effect	Δscore
2:218269962:TCA:T	donor_loss	1.0000
2:218269963:CAC:C	donor_loss	1.0000
2:218269964:ACCT:A	donor_loss	1.0000
2:218269965:CCTGG:C	donor_loss	1.0000
2:218271545:GCCTG:G	donor_gain	1.0000
2:218271547:CTGG:C	donor_loss	1.0000
2:218271548:TGG:T	donor_loss	1.0000
2:218271549:GGTG:G	donor_loss	1.0000
2:218271550:G:GA	donor_loss	1.0000
2:218271550:G:GG	donor_gain	1.0000
2:218271551:T:G	donor_loss	1.0000
2:218272687:G:GG	donor_gain	1.0000
2:218275617:AGGAA:A	acceptor_gain	1.0000
2:218275618:GGAA:G	acceptor_gain	1.0000
2:218275619:GAA:G	acceptor_gain	1.0000
2:218275620:AA:A	acceptor_gain	1.0000
2:218275622:C:CC	acceptor_gain	1.0000
2:218275625:C:CT	acceptor_gain	1.0000
2:218275626:A:T	acceptor_gain	1.0000
2:218275630:A:AC	acceptor_gain	1.0000
2:218275630:A:C	acceptor_gain	1.0000
2:218276020:ACTT:A	donor_loss	1.0000
2:218276021:CTTA:C	donor_loss	1.0000
2:218276022:TTA:T	donor_loss	1.0000
2:218276023:TA:T	donor_loss	1.0000
2:218276024:A:AC	donor_gain	1.0000
2:218276024:ACC:A	donor_loss	1.0000
2:218276025:C:CG	donor_gain	1.0000
2:218276025:CCAG:C	donor_gain	1.0000
2:218276025:CCAGG:C	donor_gain	1.0000

AlphaMissense

2456 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:218342121:A:T	D253V	1.000
2:218342121:A:C	D253A	0.999
2:218342129:T:C	F256L	0.999
2:218342131:C:A	F256L	0.999
2:218342131:C:G	F256L	0.999
2:218344847:T:C	F342L	0.999
2:218344849:C:A	F342L	0.999
2:218344849:C:G	F342L	0.999
2:218340070:A:C	S132R	0.998
2:218340072:C:A	S132R	0.998
2:218340072:C:G	S132R	0.998
2:218341536:A:C	D176A	0.998
2:218341536:A:T	D176V	0.998
2:218341537:C:A	D176E	0.998
2:218341537:C:G	D176E	0.998
2:218342050:C:A	H229Q	0.998
2:218342050:C:G	H229Q	0.998
2:218342112:T:C	F250S	0.998
2:218342117:G:T	G252W	0.998
2:218342118:G:T	G252V	0.998
2:218342121:A:G	D253G	0.998
2:218342122:C:A	D253E	0.998
2:218342122:C:G	D253E	0.998
2:218343580:T:A	W288R	0.998
2:218343580:T:C	W288R	0.998
2:218344484:T:C	F300L	0.998
2:218344485:T:C	F300S	0.998
2:218344486:T:A	F300L	0.998
2:218344486:T:G	F300L	0.998
2:218344843:C:A	N340K	0.998

dbSNP variants (sampled 300 via entrez): RS1000000147 (2:218324894 C>T), RS1000013463 (2:218282245 C>G,T), RS1000035733 (2:218339944 A>C,G), RS1000087856 (2:218335803 A>C), RS1000147506 (2:218305798 G>A), RS1000148135 (2:218325894 C>T), RS1000176624 (2:218291309 CAGAG>C,CAG), RS1000178701 (2:218306130 G>A), RS1000283953 (2:218297774 C>T), RS1000286203 (2:218276914 G>A), RS1000296352 (2:218341502 G>A,C,T), RS1000339013 (2:218271072 C>T), RS1000370456 (2:218270761 C>G,T), RS1000454258 (2:218347151 G>A), RS1000474687 (2:218284052 TACTC>T)

Disease associations

OMIM: gene MIM:609023 | disease phenotypes: MIM:118800

GenCC curated gene-disease

Disease	Classification	Inheritance
paroxysmal nonkinesigenic dyskinesia 1	Strong	Autosomal dominant
Tourette syndrome	Limited	Autosomal dominant

Mondo (4): paroxysmal nonkinesigenic dyskinesia (MONDO:0700088), paroxysmal nonkinesigenic dyskinesia 1 (MONDO:0700089), (MONDO:0007326), Tourette syndrome (MONDO:0007661)

Orphanet (2): Paroxysmal non-kinesigenic dyskinesia (Orphanet:98810), Moyamoya angiopathy (Orphanet:477768)

HPO phenotypes

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

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000211	Trismus
HP:0000273	Facial grimacing
HP:0000473	Torticollis
HP:0001260	Dysarthria
HP:0001266	Choreoathetosis
HP:0001332	Dystonia
HP:0001387	Joint stiffness
HP:0002015	Dysphagia
HP:0002063	Rigidity
HP:0002072	Chorea
HP:0002094	Dyspnea
HP:0002167	Abnormal speech pattern
HP:0002268	Paroxysmal dystonia
HP:0002411	Myokymia
HP:0002487	Hyperkinetic movements
HP:0003324	Generalized muscle weakness
HP:0003593	Infantile onset
HP:0004305	Involuntary movements
HP:0007098	Paroxysmal choreoathetosis
HP:0007166	Paroxysmal dyskinesia
HP:0011463	Childhood onset
HP:0025401	Staring gaze
HP:0100660	Dyskinesia

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST001725_74	Inflammatory bowel disease	4.000000e-12
GCST004131_76	Inflammatory bowel disease	2.000000e-07
GCST004607_251	Plateletcrit	6.000000e-10
GCST004610_53	White blood cell count	2.000000e-10
GCST004612_55	High light scatter reticulocyte percentage of red cells	4.000000e-17
GCST004613_86	Sum neutrophil eosinophil counts	9.000000e-11
GCST004614_136	Granulocyte count	6.000000e-11
GCST004620_51	Sum basophil neutrophil counts	1.000000e-11
GCST004621_53	Red cell distribution width	2.000000e-13
GCST004625_57	Monocyte count	1.000000e-16
GCST004626_24	Myeloid white cell count	2.000000e-12
GCST004629_29	Neutrophil count	1.000000e-11
GCST004895_2	Colorectal cancer	2.000000e-09
GCST006804_138	Red cell distribution width	3.000000e-10
GCST007267_191	Systolic blood pressure	1.000000e-08
GCST007856_77	Colorectal cancer or advanced adenoma	2.000000e-11
GCST008163_184	Height	1.000000e-07
GCST010244_387	Triglyceride levels	2.000000e-10
GCST012227_1242	Hip circumference adjusted for BMI	1.000000e-09
GCST012227_1243	Hip circumference adjusted for BMI	3.000000e-08
GCST90000025_873	Appendicular lean mass	3.000000e-27
GCST90002386_274	High light scatter reticulocyte percentage of red cells	9.000000e-27
GCST90002387_59	Immature fraction of reticulocytes	7.000000e-13
GCST90002400_342	Plateletcrit	4.000000e-23
GCST90002404_34	Red cell distribution width	8.000000e-42
GCST90002405_150	Reticulocyte count	1.000000e-22
GCST90002406_68	Reticulocyte fraction of red cells	2.000000e-26
GCST90013406_179	Liver enzyme levels (alkaline phosphatase)	3.000000e-18
GCST90020028_757	Hip circumference adjusted for BMI	8.000000e-11
GCST90020028_759	Hip circumference adjusted for BMI	5.000000e-10

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0007985	platelet crit
EFO:0007986	reticulocyte count
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0009188	Red cell distribution width
EFO:0005091	monocyte count
EFO:0006335	systolic blood pressure
EFO:0004530	triglyceride measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D005879	Tourette Syndrome	C10.228.140.079.898; C10.228.662.825.800; C10.574.500.850; C16.320.400.820; F03.625.992.850

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Acetaminophen	decreases expression	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Nickel	decreases expression	2
Valproic Acid	decreases expression, decreases methylation, increases expression	2
Aflatoxin B1	increases methylation	2
bisphenol A	affects cotreatment, increases methylation, decreases methylation	1
salinomycin	decreases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
cadmium acetate	increases expression	1
aflatoxin B2	decreases methylation	1
nickel sulfate	increases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	increases methylation	1
jinfukang	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Zoledronic Acid	increases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Calcitriol	decreases expression	1
Estradiol	increases expression	1
Methyl Methanesulfonate	decreases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Dihydrotestosterone	increases expression	1
Thiram	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2BA	Abcam HeLa PNKD KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00226824	PHASE4	TERMINATED	Safety Study of Galantamine in Tic Disorders
NCT00241176	PHASE4	COMPLETED	Open Label Trial of Aripiprazole in Children and Adolescents With Tourette’s Disorder
NCT00370838	PHASE4	COMPLETED	Comparison of Keppra and Clonidine in the Treatment of Tics
NCT01018056	PHASE4	COMPLETED	Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission
NCT01547000	PHASE4	COMPLETED	Guanfacine in Children With Tic Disorders
NCT03239210	PHASE4	COMPLETED	Effects of Ondansetron in Obsessive-compulsive and Tic Disorders
NCT00004376	PHASE3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Guanfacine for Tourette Syndrome and Attention Deficit Hyperactivity Disorder
NCT00206323	PHASE3	COMPLETED	A Randomized, Placebo-controlled, Tourette Syndrome Study.
NCT00206336	PHASE3	COMPLETED	An Open-label Study to Determine the Efficacy and Safety of Topiramate in the Treatment of Tourette Syndrome.
NCT00478842	PHASE3	COMPLETED	Pallidal Stimulation and Gilles de la Tourette Syndrome
NCT00681863	PHASE3	TERMINATED	Open-label Extension Study of Pramipexole in the Treatment of Children and Adolescents With Tourette Syndrome
NCT01501695	PHASE3	COMPLETED	Phase III Study of 5LGr to Treat Tic Disorder
NCT03087201	PHASE3	COMPLETED	CANNAbinoids in the Treatment of TICS (CANNA-TICS)
NCT03487783	PHASE3	COMPLETED	Aripiprazole Oral Solution in the Treatment of Children and Adolescents With Tourette’s Syndrome
NCT03567291	PHASE3	TERMINATED	Evaluation of Safety and Tolerability of Long-term TEV-50717 (Deutetrabenazine) for Treatment of Tourette Syndrome in Children and Adolescents
NCT03571256	PHASE3	COMPLETED	A Study to Test if TEV-50717 is Effective in Relieving Tics Associated With Tourette Syndrome (TS)
NCT06021522	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Long-term Safety of Ecopipam Tablets in Children, Adolescents and Adults With Tourette’s Disorder
NCT00004393	PHASE2	COMPLETED	Phase II Double Blind Placebo Controlled Trial of Risperidone in Tourette Syndrome
NCT00004652	PHASE2	COMPLETED	Phase II Pilot Controlled Study of Short Vs Longer Term Pimozide (Orap) Therapy in Tourette Syndrome
NCT00231985	PHASE2	COMPLETED	Effectiveness of Behavior Therapy and Psychosocial Therapy for the Treatment of Tourette Syndrome and Chronic Tic Disorder
NCT00311909	PHASE2	COMPLETED	Thalamic Deep Brain Stimulation for Tourette Syndrome
NCT00529308	PHASE2	COMPLETED	Transcranial Magnetic Stimulation (TMS) for Individuals With Tourette’s Syndrome
NCT00558467	PHASE2	COMPLETED	Pramipexole Pilot Phase II Study in Children and Adolescents With Tourette Disorder According to DSM-IV Criteria
NCT01043549	PHASE2	TERMINATED	Repetitive Transcranial Magnetic Stimulation of the Posterior Parietal Cortex in Patients Suffering From Gilles de la Tourette Syndrome
NCT01133353	PHASE2	WITHDRAWN	A Study of the Effectiveness and Safety of Tetrabenazine MR in Pediatric Subjects With Tourette’s Syndrome
NCT01475383	PHASE2	WITHDRAWN	Study Evaluating The Safety And Efficacy Of PF-03654746 In Adult Subjects With Tourette’s Syndrome
NCT01647269	PHASE2	COMPLETED	A Trial of Bilateral Deep Brain Stimulation to the Globus Pallidus Internum in Tourette Syndrome
NCT01904773	PHASE2	COMPLETED	Safety, Tolerability, Pharmacokinetic, and Efficacy Study of AZD5213 in Adolescents With Tourette’s Disorder
NCT02102698	PHASE2	COMPLETED	Ecopipam Treatment of Tourette’s Syndrome in Subjects 7-17 Years
NCT02217007	PHASE2	WITHDRAWN	A Trial Evaluating the Efficacy, Safety, and Pharmacokinetics of SNC-102 in Subjects With Tourette Syndrome
NCT02247206	PHASE2	COMPLETED	VoIP Delivered Behavior Therapy for Tourette Syndrome
NCT02581865	PHASE2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Adults With Tourette Syndrome
NCT02619084	PHASE2	COMPLETED	Subthalamic Stimulation in Tourette’s Syndrome
NCT02679079	PHASE2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Children and Adolescents With Tourette Syndrome
NCT02879578	PHASE2	COMPLETED	Safety and Tolerability Study of NBI-98854 for the Treatment of Subjects With Tourette Syndrome
NCT03066193	PHASE2	COMPLETED	Efficacy of a Therapeutic Combination of Dronabinol and PEA for Tourette Syndrome
NCT03247244	PHASE2	TERMINATED	Safety and Efficacy of Cannabis in Tourette Syndrome
NCT03325010	PHASE2	COMPLETED	Safety, Tolerability, and Efficacy of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome
NCT03444038	PHASE2	COMPLETED	Open-Label Safety and Tolerability Study of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome