DPYSL2

Summary

DPYSL2 (dihydropyrimidinase like 2, HGNC:3014) is a protein-coding gene on chromosome 8p21.2, encoding Dihydropyrimidinase-related protein 2 (Q16555). Plays a role in neuronal development and polarity, as well as in axon growth and guidance, neuronal growth cone collapse and cell migration.

This gene encodes a member of the collapsin response mediator protein family. Collapsin response mediator proteins form homo- and hetero-tetramers and facilitate neuron guidance, growth and polarity. The encoded protein promotes microtubule assembly and is required for Sema3A-mediated growth cone collapse, and also plays a role in synaptic signaling through interactions with calcium channels. This gene has been implicated in multiple neurological disorders, and hyperphosphorylation of the encoded protein may play a key role in the development of Alzheimer’s disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 1808 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 655 total — 15 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_001197293

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3014
Approved symbol	DPYSL2
Name	dihydropyrimidinase like 2
Location	8p21.2
Locus type	gene with protein product
Status	Approved
Aliases	DRP-2, DHPRP2, CRMP2, DRP2
Ensembl gene	ENSG00000092964
Ensembl biotype	protein_coding
OMIM	602463
Entrez	1808

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000311151, ENST00000474808, ENST00000493789, ENST00000521913, ENST00000521983, ENST00000523027, ENST00000523093, ENST00000523690

RefSeq mRNA: 3 — MANE Select: NM_001197293 NM_001197293, NM_001244604, NM_001386

CCDS: CCDS59096, CCDS6051, CCDS83268

Canonical transcript exons

ENST00000521913 — 14 exons

Exon	Start	End
ENSE00001616779	26643950	26644091
ENSE00001617914	26624143	26624307
ENSE00001643130	26643439	26643595
ENSE00001694723	26652257	26652436
ENSE00001703598	26647630	26647800
ENSE00001780215	26653232	26653397
ENSE00002102109	26514031	26514679
ENSE00002128447	26655615	26658175
ENSE00002154917	26583799	26583983
ENSE00003485309	26581969	26582057
ENSE00003514271	26627215	26627295
ENSE00003514643	26627872	26627940
ENSE00003591912	26634780	26634900
ENSE00003645192	26626617	26626678

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 99.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 213.2918 / max 36743.6016, expressed in 1814 samples.

FANTOM5 promoters (22 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88069	110.9171	1773
88105	71.7309	1740
88071	6.5943	1307
88057	5.5169	927
88068	5.0344	1566
88073	3.6385	890
88072	1.9409	725
88064	1.1724	768
88056	1.0956	348
88065	1.0036	564

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior vagus X ganglion	UBERON:0005363	99.90	gold quality
subthalamic nucleus	UBERON:0001906	99.89	gold quality
substantia nigra pars compacta	UBERON:0001965	99.89	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.89	gold quality
lateral globus pallidus	UBERON:0002476	99.88	gold quality
superior vestibular nucleus	UBERON:0007227	99.88	gold quality
pons	UBERON:0000988	99.87	gold quality
cerebellar vermis	UBERON:0004720	99.86	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.85	gold quality
medulla oblongata	UBERON:0001896	99.84	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.84	gold quality
paraflocculus	UBERON:0005351	99.84	gold quality
ventral tegmental area	UBERON:0002691	99.82	gold quality
middle frontal gyrus	UBERON:0002702	99.81	gold quality
CA1 field of hippocampus	UBERON:0003881	99.79	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.78	gold quality
parietal lobe	UBERON:0001872	99.77	gold quality
corpus callosum	UBERON:0002336	99.77	gold quality
cranial nerve II	UBERON:0000941	99.76	gold quality
postcentral gyrus	UBERON:0002581	99.75	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.75	gold quality
frontal pole	UBERON:0002795	99.74	gold quality
dorsal root ganglion	UBERON:0000044	99.68	gold quality
superior frontal gyrus	UBERON:0002661	99.67	gold quality
globus pallidus	UBERON:0001875	99.64	gold quality
orbitofrontal cortex	UBERON:0004167	99.64	gold quality
adult organism	UBERON:0007023	99.64	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.63	gold quality
inferior olivary complex	UBERON:0002127	99.61	gold quality
entorhinal cortex	UBERON:0002728	99.59	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	39.49
E-CURD-112	yes	13.65
E-MTAB-7316	yes	12.99
E-GEOD-84465	yes	12.00
E-GEOD-125970	yes	8.96
E-GEOD-83139	yes	8.91
E-MTAB-6678	yes	8.47
E-MTAB-9801	yes	8.23
E-GEOD-86618	no	545.88
E-MTAB-10137	no	519.36
E-ENAD-27	no	10.32
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA1, GATA2, PAX3, SMAD1, SMAD4, SP1

miRNA regulators (miRDB)

142 targeting DPYSL2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-7-1-3P	99.91	71.53	4384

Literature-anchored findings (GeneRIF, showing 40)

• Aberrant expression of dihydropyrimidinase related proteins-2,-3 and -4 in fetal Down syndrome brain. (PMID:11771764)
• CRMP-1 and CRMP-2 have a role in RhoA-dependent signaling, through interaction with and regulation of ROKalpha (PMID:12482610)
• No significant associations were found between five polymorphisms of the DRP-2 gene and Bipolar Disorder, nor were associations detected between either of the polymorphisms and bipolar subtypes I and II. (PMID:12951196)
• Here we show that glial cell line-derived neurotrophic factor (GDNF) enhances CRMP-2 expression in TGW human neuroblastoma cells via activation of RET receptor tyrosine kinase. (PMID:15207709)
• significant decrease of crmp-2 protein may represent or underlie impaired neuronal plasticity, neurodegeneration, wiring of the brain in mesial temporal lobe epilepsy (PMID:15672539)
• A significant association was found between a single nucleotide polymorphism of the DRP-2 gene and schizophrenia in a North American sample. (PMID:15858820)
• CRMP-2 transports the Sra-1/WAVE1 complex to axons in a kinesin-1-dependent manner and thereby regulates axon outgrowth and formation (PMID:16260607)
• GSK3 alters phosphorylation of CRMP-1, -2, and -4 isoforms (PMID:16611631)
• collapsin response mediator protein-2 transcriptional activity is inhibited by all-trans-retinoic acid during SH-SY5Y neuroblastoma cell differentiation (PMID:17229153)
• These observations implicate hyperphosphorylation of CRMP2 as an early event in the development of AD and suggest that it can be induced by a severe APP over-expression and/or processing defect. (PMID:17683481)
• results indicate that that CRMP-2 may be a novel colorectal cancer biomarker (PMID:18203259)
• association of neurofibromin and CRMP-2 is essential for neuronal cell differentiation (PMID:18218617)
• relative resistance to phosphatases might be a common feature of Cdk5 substrates and could contribute to the hyperphosphorylation of CRMP2 and Tau observed in Alzheimer disease (PMID:18460467)
• This protein has been found differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19110265)
• Data suggest that collapsin response mediator protein-2 (CRMP-2) is a novel calmodulin-binding protein and that CaM binding may play an important role in regulating CRMP-2 functions. (PMID:19151921)
• This protein has been found differentially expressed in the Wernicke’s Area from patients with schizophrenia. (PMID:19405953)
• Given that CRMP-2 is a key regulator of axon elongation, this interference with cytoplasmic dynein function by CRMP-2 might have an important role in axon formation, and neuronal development (PMID:19659462)
• CRMP2 as a tubulin direct binder may be a GTPase-activating protein (GAP) of tubulin in neurite formation and its GAP activity may be regulated by an intramolecular interaction with an N-terminal inhibitory region. (PMID:19666111)
• This protein has been found differentially expressed in the anterior cingulate cortex from patients with schizophrenia (PMID:20381070)
• DPYSL2 does not have a major function in schizophrenia in Japanese subjects. (PMID:20414250)
• Data provide the first trafficking regulatory role for Crmp2 in non-neuronal cells and support a model in which Crmp2 is an important endocytic regulatory protein that links MICAL-L1.EHD1-based vesicular transport to dynein motors. (PMID:20801876)
• This review discusses the essential biology of CRMP2 in the context of nascent data implicating CRMP2 perturbations as either a correlate of, or plausible contributor to, diverse neuropathologies. (PMID:21271304)
• Data support DPYSL2 and the surrounding genomic region as a susceptibility locus for schizophrenia. (PMID:21302347)
• CRMP2 hyperphosphorylation is speci fi c to Alzheimer’s disease and is not a common event in all forms of dementia and neurodegeneration, especially other tauopathies. (PMID:21860090)
• HTLV-1 has the capacity to influence the CRMP2/PI3K/Akt axis thus to positively control cytoskeleton organization and lymphocyte migration. (PMID:22227566)
• CRMP2 controls dendritic projection; the phosphorylation of CRMP2 at Ser522 is essential for proper dendritic field organization for axonal guidance and spine development . (PMID:22279220)
• a new insight into CRMP-2 as a controller of myosin II-mediated cellular functions through the inhibition of ROCK II in nonneuronal cells (PMID:22431514)
• findings suggest a major role of phosphorylated CRMP-2 as a mechanism involved in process retraction induced by reactive oxygen species (PMID:22443207)
• No Alzheimer disease-associated differences in CNP and DPYSL2 promoter DNA methylation were observed. (PMID:22954668)
• High levels of nuclear phosphorylated CRMP-2 is associated with lung cancer. (PMID:23023514)
• Deletion analysis of CRMP-2 identified a 51 amino acid sequence in the C-terminus that is required for targeting to the basal body and primary cilium. This domain contains GSK-3beta phosphorylation sites. (PMID:23185275)
• Reduced CRMP2 expression and elevated expression of nuclear phosphorylated CRMP2 may be associated with breast cancer progression. (PMID:23381229)
• a novel regulatory mechanism that utilizes CRMP2 SUMOylation to choreograph NaV1.7 trafficking. (PMID:23836888)
• genetic variants in DPYSL2 may play a role in susceptibility to alcohol dependence. (PMID:23846846)
• CRMP-2-dependent regulation of ROCK II activity is mediated through interaction of the CRMP-2L N terminus with the ROCK II catalytic domain as well as by GSK3-dependent phosphorylation of CRMP-2. (PMID:24036111)
• A specific and reversible intermolecular Cys-504-Cys-504 dithiol-disulfide switch in homotetrameric CRMP2 determines two conformations of the quaternary CRMP2 complex that controls axonal outgrowth and thus neuronal development. (PMID:24133216)
• High dihydropyrimidinase-related protein 2 expression is associated with lung cancer. (PMID:24518087)
• Levels of total GSK3 were decreased in the Huntington disease-affected frontal cortex and this correlated with decreased phosphorylated CRMP2. (PMID:24634145)
• Changes for CRMP2, TCP1epsilon, TPM2 and 14-3-3gamma were confirmed in experimental tumors and in a series of 28 human SI-NETs. (PMID:25224486)
• Functional variants in DPYSL2 sequence increase risk of schizophrenia and suggest a link to mTOR signaling (PMID:25416705)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	dpysl2b	ENSDARG00000032083
danio_rerio		ENSDARG00000038974
mus_musculus	Dpysl2	ENSMUSG00000022048
rattus_norvegicus	Dpysl2	ENSRNOG00000009625

Paralogs (5): CRMP1 (ENSG00000072832), DPYSL3 (ENSG00000113657), DPYS (ENSG00000147647), DPYSL4 (ENSG00000151640), DPYSL5 (ENSG00000157851)

Protein

Protein identifiers

Dihydropyrimidinase-related protein 2 — Q16555 (reviewed: Q16555)

Alternative names: Collapsin response mediator protein 2, N2A3, Unc-33-like phosphoprotein 2

All UniProt accessions (3): Q16555, A0A1C7CYX9, E5RFU4

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in neuronal development and polarity, as well as in axon growth and guidance, neuronal growth cone collapse and cell migration. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. May play a role in endocytosis.

Subunit / interactions. Homotetramer, and heterotetramer with CRMP1, DPYSL3, DPYSL4 or DPYSL5. Interacts through its C-terminus with the C-terminus of CYFIP1/SRA1. Interacts with HTR4. Interacts with CLN6. Interacts with MICALL1.

Subcellular location. Cytoplasm. Cytosol. Cytoskeleton. Membrane.

Tissue specificity. Ubiquitous.

Post-translational modifications. 3F4, a monoclonal antibody which strongly stains neurofibrillary tangles in Alzheimer disease brains, specifically labels DPYSL2 when phosphorylated on Ser-518, Ser-522 and Thr-509. Phosphorylation at Thr-514 by GSK3B abolishes tubulin-binding leading to destabilization of microtubule assembly in axons and neurodegeneration. Phosphorylation by DYRK2 at Ser-522 is required for subsequent phosphorylation by GSK3B.

Similarity. Belongs to the metallo-dependent hydrolases superfamily. Hydantoinase/dihydropyrimidinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q16555-1	1	yes
Q16555-2	2

RefSeq proteins (3): NP_001184222, NP_001231533, NP_001377 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006680	Amidohydro-rel	Domain
IPR011059	Metal-dep_hydrolase_composite	Homologous_superfamily
IPR011778	Hydantoinase/dihydroPyrase	Family
IPR032466	Metal_Hydrolase	Homologous_superfamily
IPR050378	Metallo-dep_Hydrolases_sf	Family

Pfam: PF01979

UniProt features (80 total): modified residue 20, strand 20, helix 19, mutagenesis site 9, turn 6, sequence variant 2, chain 1, region of interest 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
5LXX	X-RAY DIFFRACTION	1.25
5MKV	X-RAY DIFFRACTION	1.8
5YZ5	X-RAY DIFFRACTION	1.8
7X68	X-RAY DIFFRACTION	1.8
5X1A	X-RAY DIFFRACTION	1.82
2VM8	X-RAY DIFFRACTION	1.9
6JVB	X-RAY DIFFRACTION	2
5X1C	X-RAY DIFFRACTION	2.1
5X1D	X-RAY DIFFRACTION	2.2
6JV9	X-RAY DIFFRACTION	2.26
5YZA	X-RAY DIFFRACTION	2.3
2GSE	X-RAY DIFFRACTION	2.4
5MLE	X-RAY DIFFRACTION	2.48
8DNM	ELECTRON MICROSCOPY	2.76
5YZB	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16555-F1	90.49	0.82

Functional residue map

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

Post-translational modifications (20): 507, 509, 512, 514, 517, 518, 521, 522, 537, 540, 542, 555, 565, 32, 258, 259, 431, 465, 499, 504

Mutagenesis-validated functional residues (9):

Position	Phenotype
71	inhibits axon outgrowth formation in hippocampal neurons and decreases binding to cyfip1.
507	no effect.
509	greatly diminishes binding to 3f4 antibody.
512	no effect.
514	no effect.
517	no effect.
518	greatly diminishes binding to 3f4 antibody.
521	no effect.
522	greatly diminishes binding to 3f4 antibody.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-399956	CRMPs in Sema3A signaling
R-HSA-437239	Recycling pathway of L1

MSigDB gene sets: 444 (showing top): RNGTGGGC_UNKNOWN, VERHAAK_AML_WITH_NPM1_MUTATED_DN, MYAATNNNNNNNGGC_UNKNOWN, E2F_Q4_01, TGCACTT_MIR519C_MIR519B_MIR519A, ZHAN_MULTIPLE_MYELOMA_MF_UP, GCANCTGNY_MYOD_Q6, GOBP_VESICLE_MEDIATED_TRANSPORT, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, GGCNKCCATNK_UNKNOWN, GOBP_PYRIMIDINE_NUCLEOBASE_METABOLIC_PROCESS, SREBP1_02, HERNANDEZ_MITOTIC_ARREST_BY_DOCETAXEL_1_DN, GOBP_CELL_CELL_SIGNALING

GO Biological Process (7): nucleobase-containing compound metabolic process (GO:0006139), endocytosis (GO:0006897), cytoskeleton organization (GO:0007010), signal transduction (GO:0007165), nervous system development (GO:0007399), cell differentiation (GO:0030154), regulation of neuron projection development (GO:0010975)

GO Molecular Function (7): dihydropyrimidinase activity (GO:0004157), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amides (GO:0016812), identical protein binding (GO:0042802), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds (GO:0016810), protein kinase binding (GO:0019901)

GO Cellular Component (16): cytosol (GO:0005829), plasma membrane (GO:0005886), cilium (GO:0005929), microtubule cytoskeleton (GO:0015630), extracellular exosome (GO:0070062), mitotic spindle (GO:0072686), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), microtubule (GO:0005874), postsynaptic density (GO:0014069), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), neuronal cell body (GO:0043025), Schaffer collateral - CA1 synapse (GO:0098685), plasma membrane bounded cell projection (GO:0120025)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Semaphorin interactions	1
L1CAM interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
neuron projection	2
primary metabolic process	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
organelle organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
system development	1
cellular developmental process	1
neuron projection development	1
regulation of plasma membrane bounded cell projection organization	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amides	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds	1
protein binding	1
binding	1
catalytic activity	1
hydrolase activity	1
kinase binding	1
cytoplasm	1
membrane	1
cell periphery	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cytoskeleton	1
extracellular vesicle	1
spindle	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
asymmetric synapse	1
postsynaptic specialization	1
dendritic tree	1

Protein interactions and networks

STRING

2510 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DPYSL2	NUMBL	Q9Y6R0	946
DPYSL2	NUMB	P49757	946
DPYSL2	CACNA1B	Q00975	921
DPYSL2	RAB27A	P51159	862
DPYSL2	GSK3B	P49841	848
DPYSL2	CDK5	Q00535	809
DPYSL2	RAB27B	O00194	753
DPYSL2	DISC1	Q9NRI5	728
DPYSL2	KLC1	Q07866	721
DPYSL2	MAP1B	P46821	718
DPYSL2	GRIN2A	Q12879	710
DPYSL2	TXN	P10599	702
DPYSL2	SCN9A	Q15858	686
DPYSL2	SEMA3A	Q14563	679
DPYSL2	GDA	Q9Y2T3	678

IntAct

170 interactions, top by confidence:

A	B	Type	Score
DPYSL2	DPYSL5	psi-mi:“MI:0915”(physical association)	0.900
DPYSL5	DPYSL2	psi-mi:“MI:0915”(physical association)	0.900
DPYSL2	DPYSL2	psi-mi:“MI:0915”(physical association)	0.850
DPYSL2	GORASP2	psi-mi:“MI:0915”(physical association)	0.830
GORASP2	DPYSL2	psi-mi:“MI:0915”(physical association)	0.830
CDC23	BUB1B	psi-mi:“MI:0914”(association)	0.790
DPYSL3	DPYSL2	psi-mi:“MI:0915”(physical association)	0.750
DPYSL2	DPYSL3	psi-mi:“MI:0915”(physical association)	0.750
DPYSL3	DPYSL2	psi-mi:“MI:0915”(physical association)	0.740

BioGRID (300): DPYSL2 (Two-hybrid), DPYSL3 (Two-hybrid), GORASP2 (Two-hybrid), DPYSL5 (Two-hybrid), DPYSL2 (Affinity Capture-MS), DPYSL2 (Affinity Capture-MS), DPYSL2 (Affinity Capture-MS), DPYSL2 (Affinity Capture-MS), DPYSL2 (Affinity Capture-MS), DPYSL2 (Affinity Capture-MS), DPYSL2 (Affinity Capture-MS), DPYSL2 (Affinity Capture-MS), DPYSL2 (Affinity Capture-MS), DPYSL2 (Affinity Capture-RNA), ARFIP1 (Co-fractionation)

ESM2 similar proteins: A1A4L8, A2VDS1, A5GFY8, A5GFZ6, A6H791, A7MBC0, D4AAT7, E1BNQ4, E2QUI9, O14531, O35098, O43175, O75600, O95396, O95571, P13439, P31754, P38918, P43353, Q14117, Q16555, Q3T094, Q42942, Q4V831, Q4V9P6, Q5BJY6, Q5R7M2, Q5R824, Q5R9Y6, Q5RDK5, Q5U4Q9, Q5ZKP6, Q60HD7, Q62951, Q66IQ6, Q68FT9, Q6AY46, Q6P0U0, Q80XC2, Q8IW45

Diamond homologs: A1AF64, A7ZQY1, A7ZXG5, A8A415, B1ITC8, B1IZ89, B1XEG2, B6I0G2, B6I707, B7L7D8, B7LF59, B7LYD8, B7M4L5, B7MM60, B7MZ27, B7N7B8, B7N966, B7NW14, B7UHS3, C5A0E6, O02675, O08553, O13022, O14531, O35098, O69809, P47942, P81006, P97427, Q02C42, Q0TDX8, Q14117, Q14194, Q14195, Q16555, Q18677, Q1AS71, Q1J391, Q1R7F8, Q21773

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
CDK5	“down-regulates activity”	DPYSL2	phosphorylation
GSK3B	“down-regulates activity”	DPYSL2	phosphorylation
DPYSL2	up-regulates	Microtubule_polimerization
DPYSL2	up-regulates	Neurite_outgrowth
TTBK1	“up-regulates activity”	DPYSL2	phosphorylation
ROCK2	up-regulates	DPYSL2	phosphorylation
ROCK1	unknown	DPYSL2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 116 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Antimicrobial mechanism of IFN-stimulated genes	5	11.9×	6e-03
PKR-mediated signaling	6	10.2×	4e-03
Transcriptional regulation of granulopoiesis	6	9.1×	6e-03
Separation of Sister Chromatids	8	5.8×	6e-03
Cellular responses to stress	11	4.9×	3e-03
Cellular responses to stimuli	12	4.5×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	5
Uncertain significance	345
Likely benign	180
Benign	51

Top pathogenic / likely-pathogenic (20)

Variant ID	HGVS	Classification
1360406	NM_001939.3(DRP2):c.1294G>T (p.Glu432Ter)	Pathogenic
1451551	NM_001939.3(DRP2):c.2350G>T (p.Glu784Ter)	Pathogenic
1454533	NM_001939.3(DRP2):c.2512_2524del (p.Glu838fs)	Pathogenic
1909090	NM_001939.3(DRP2):c.424A>T (p.Lys142Ter)	Pathogenic
2000341	NM_001939.3(DRP2):c.1738G>T (p.Glu580Ter)	Pathogenic
2422510	NC_000023.10:g.(?100499986)(100662891_?)del	Pathogenic
2424325	NC_000023.10:g.(?100486637)(100515610_?)del	Pathogenic
2696145	NM_001939.3(DRP2):c.2356C>T (p.Gln786Ter)	Pathogenic
2792806	NM_001939.3(DRP2):c.2307del (p.Phe769fs)	Pathogenic
2809124	NM_001939.3(DRP2):c.2158C>T (p.Arg720Ter)	Pathogenic
2967325	NM_001939.3(DRP2):c.958C>T (p.Arg320Ter)	Pathogenic
3015752	NM_001939.3(DRP2):c.94C>T (p.Arg32Ter)	Pathogenic
3606919	NM_001939.3(DRP2):c.2065C>T (p.Arg689Ter)	Pathogenic
4730160	NM_001939.3(DRP2):c.2327del (p.Ser776fs)	Pathogenic
4734175	NM_001939.3(DRP2):c.521del (p.Pro174fs)	Pathogenic
1491516	NM_001939.3(DRP2):c.2114+1G>A	Likely pathogenic
225088	NM_001197293.3(DPYSL2):c.357C>A (p.Ser119Arg)	Likely pathogenic
2839242	NM_001939.3(DRP2):c.1677_1698+44del	Likely pathogenic
3684454	NM_001939.3(DRP2):c.1866-1G>A	Likely pathogenic
493540	NM_001939.3(DRP2):c.379del (p.Ala127fs)	Likely pathogenic

SpliceAI

5599 predictions. Top by Δscore:

Variant	Effect	Δscore
8:26581967:A:AG	acceptor_gain	1.0000
8:26581967:A:C	acceptor_loss	1.0000
8:26581967:AGAGC:A	acceptor_gain	1.0000
8:26581968:G:GG	acceptor_gain	1.0000
8:26581968:GA:G	acceptor_gain	1.0000
8:26581968:GAGC:G	acceptor_gain	1.0000
8:26581968:GAGCG:G	acceptor_gain	1.0000
8:26582056:AAG:A	donor_loss	1.0000
8:26582057:AG:A	donor_loss	1.0000
8:26582058:G:GG	donor_gain	1.0000
8:26582059:TAAG:T	donor_loss	1.0000
8:26582060:AAGT:A	donor_loss	1.0000
8:26583797:A:AG	acceptor_gain	1.0000
8:26583798:G:GG	acceptor_gain	1.0000
8:26583798:GGC:G	acceptor_gain	1.0000
8:26583798:GGCAA:G	acceptor_gain	1.0000
8:26583915:G:T	donor_gain	1.0000
8:26583979:GATCA:G	donor_gain	1.0000
8:26583984:G:GG	donor_gain	1.0000
8:26584019:G:GT	donor_gain	1.0000
8:26624138:TCTA:T	acceptor_loss	1.0000
8:26624139:CTA:C	acceptor_loss	1.0000
8:26624141:A:AG	acceptor_gain	1.0000
8:26624141:AGTT:A	acceptor_gain	1.0000
8:26624142:G:GT	acceptor_gain	1.0000
8:26624142:GT:G	acceptor_gain	1.0000
8:26624142:GTT:G	acceptor_gain	1.0000
8:26624142:GTTG:G	acceptor_gain	1.0000
8:26624142:GTTGA:G	acceptor_gain	1.0000
8:26624254:G:GG	donor_gain	1.0000

AlphaMissense

4445 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:26634802:G:C	R238P	1.000
8:26647672:A:C	S385R	1.000
8:26647674:C:A	S385R	1.000
8:26647674:C:G	S385R	1.000
8:26653385:T:C	F539L	1.000
8:26653387:C:A	F539L	1.000
8:26653387:C:G	F539L	1.000
8:26582003:T:A	V25D	0.999
8:26582007:T:A	N26K	0.999
8:26582007:T:G	N26K	0.999
8:26582033:T:A	I35K	0.999
8:26583873:G:A	G68E	0.999
8:26627914:G:A	G222R	0.999
8:26627914:G:C	G222R	0.999
8:26643523:C:A	A299D	0.999
8:26643972:A:C	S331R	0.999
8:26643974:T:A	S331R	0.999
8:26643974:T:G	S331R	0.999
8:26644063:G:C	R361P	0.999
8:26647685:C:A	A389D	0.999
8:26647713:A:C	K398N	0.999
8:26647713:A:T	K398N	0.999
8:26647714:G:C	G399R	0.999
8:26647715:G:A	G399D	0.999
8:26647753:T:A	W412R	0.999
8:26647753:T:C	W412R	0.999
8:26653256:C:A	R496S	0.999
8:26581982:T:C	L18P	0.998
8:26582026:G:C	A33P	0.998
8:26582033:T:G	I35R	0.998

dbSNP variants (sampled 300 via entrez): RS1000030896 (8:26603182 A>T), RS1000090048 (8:26578450 T>C), RS1000097471 (8:26650998 G>A,C), RS1000102757 (8:26592367 G>C), RS1000124443 (8:26622057 T>C), RS1000131798 (8:26616605 G>T), RS1000174077 (8:26555437 A>C), RS1000177042 (8:26645075 G>A), RS1000179789 (8:26630143 TAC>T,TACAC), RS1000194113 (8:26638525 C>G), RS1000223828 (8:26636283 T>C), RS1000249299 (8:26644706 A>T), RS1000289857 (8:26544086 A>G), RS1000291959 (8:26584496 A>G), RS1000308859 (8:26617354 G>A,T)

Disease associations

OMIM: gene MIM:602463 | disease phenotypes: MIM:118220, MIM:301500, MIM:209850, MIM:302800, MIM:302900

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease	Strong	X-linked
intellectual disability	Moderate	Autosomal dominant
schizophrenia	No Known Disease Relationship	Unknown

Mondo (8): Charcot-Marie-Tooth disease (MONDO:0015626), Charcot-Marie-Tooth disease type X (MONDO:0018994), Fabry disease (MONDO:0010526), hereditary motor and sensory neuropathy (MONDO:0015358), autism (MONDO:0005260), Charcot-Marie-Tooth disease X-linked dominant 1 (MONDO:0010549), schizophrenia (MONDO:0005090), intellectual disability (MONDO:0001071)

Orphanet (5): Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), X-linked Charcot-Marie-Tooth disease (Orphanet:64747), Fabry disease (Orphanet:324), X-linked Charcot-Marie-Tooth disease type 1 (Orphanet:101075), OBSOLETE: Hereditary motor and sensory neuropathy (Orphanet:140450)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000717	Autism

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST006190_46	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-07
GCST006193_29	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3.000000e-09
GCST006193_69	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	2.000000e-06
GCST006195_59	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	4.000000e-06
GCST006627_15	Diastolic blood pressure	2.000000e-10
GCST008522_80	Bitter alcoholic beverage consumption	5.000000e-06
GCST010703_188	Brain morphology (MOSTest)	7.000000e-11
GCST011461_5	Barrett’s esophagus or Esophageal adenocarcinoma	5.000000e-08
GCST011462_5	Barrett’s esophagus or esophageal adenocarcinoma x sex interaction (2df test)	3.000000e-07
GCST011463_1	Barrett’s esophagus or esophageal adenocarcinoma x sex interaction (1df test)	5.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0004346	neuroimaging measurement
EFO:0008343	sex interaction measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D000795	Fabry Disease	C10.228.140.163.100.435.825.200; C10.228.140.300.275.374; C14.907.253.329.374; C16.320.322.124; C16.320.565.189.435.825.200; C16.320.565.398.641.803.300; C16.320.565.595.554.825.200; C18.452.132.100.435.825.200; C18.452.584.563.641.803.300; C18.452.648.189.435.825.200; C18.452.648.398.641.803.300; C18.452.648.595.554.825.200
D015417	Hereditary Sensory and Motor Neuropathy	C10.500.300; C10.574.500.495; C10.668.829.800.300; C16.131.666.300; C16.320.400.375
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C564446	Charcot-Marie-Tooth Peroneal Muscular Atrophy and Friedreich Ataxia, Combined (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295834 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.06	Kd	8628	nM	CHEMBL5653589
5.06	ED50	8628	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148262: Binding affinity to human DPYSL2 incubated for 45 mins by Kinobead based pull down assay	kd	8.6277	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression, increases methylation	5
Particulate Matter	decreases expression, decreases reaction, increases abundance, affects cotreatment	4
trichostatin A	decreases expression, affects cotreatment	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	3
Tobacco Smoke Pollution	decreases expression	3
Cadmium Chloride	decreases expression, increases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
bisphenol S	affects cotreatment, decreases methylation, increases expression	2
Arsenic Trioxide	affects expression, increases expression	2
Acetaminophen	increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Estradiol	decreases expression, increases phosphorylation	2
Ivermectin	affects cotreatment, increases expression, decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation, decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
deoxynivalenol	decreases expression	1
lead acetate	decreases expression	1
methylselenic acid	increases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
ochratoxin A	increases expression	1
bleomycetin	decreases expression	1
benzo(e)pyrene	increases methylation	1
4-hydroxy-2-nonenal	affects binding	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118725	Binding	Binding affinity to DPYSL2 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1W4	Abcam A-549 DPYSL2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety