DCX

Summary

DCX (doublecortin, HGNC:2714) is a protein-coding gene on chromosome Xq23, encoding Neuronal migration protein doublecortin (O43602). Microtubule-associated protein required for initial steps of neuronal dispersion and cortex lamination during cerebral cortex development. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the doublecortin family. The protein encoded by this gene is a cytoplasmic protein and contains two doublecortin domains, which bind microtubules. In the developing cortex, cortical neurons must migrate over long distances to reach the site of their final differentiation. The encoded protein appears to direct neuronal migration by regulating the organization and stability of microtubules. In addition, the encoded protein interacts with LIS1, the regulatory gamma subunit of platelet activating factor acetylhydrolase, and this interaction is important to proper microtubule function in the developing cortex. Mutations in this gene cause abnormal migration of neurons during development and disrupt the layering of the cortex, leading to epilepsy, cognitive disability, subcortical band heterotopia (“double cortex” syndrome) in females and lissencephaly (“smooth brain” syndrome) in males. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1641 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lissencephaly spectrum disorders (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 350 total — 116 pathogenic, 41 likely-pathogenic
• Phenotypes (HPO): 46
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001195553

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2714
Approved symbol	DCX
Name	doublecortin
Location	Xq23
Locus type	gene with protein product
Status	Approved
Aliases	SCLH, DC, LISX, DBCN, XLIS
Ensembl gene	ENSG00000077279
Ensembl biotype	protein_coding
OMIM	300121
Entrez	1641

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 14 protein_coding

ENST00000356220, ENST00000358070, ENST00000371993, ENST00000468911, ENST00000488120, ENST00000496551, ENST00000635795, ENST00000636035, ENST00000636381, ENST00000637453, ENST00000637570, ENST00000680476, ENST00000706842, ENST00000962099

RefSeq mRNA: 11 — MANE Select: NM_001195553 NM_000555, NM_001195553, NM_001369370, NM_001369371, NM_001369372, NM_001369373, NM_001369374, NM_001410715, NM_178151, NM_178152, NM_178153

CCDS: CCDS14557, CCDS14558, CCDS83483, CCDS94652, CCDS94653, CCDS94654

Canonical transcript exons

ENST00000636035 — 7 exons

Exon	Start	End
ENSE00000830382	111330904	111331041
ENSE00001853393	111412138	111412192
ENSE00003489450	111400990	111401330
ENSE00003539076	111333051	111333153
ENSE00003545517	111410035	111410420
ENSE00003795569	111312639	111312736
ENSE00003900373	111293779	111301743

Expression profiles

Bgee: expression breadth ubiquitous, 114 present calls, max score 99.50.

FANTOM5 (CAGE): breadth broad, TPM avg 7.0982 / max 1426.6261, expressed in 317 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200192	6.1625	313
200191	0.2196	34
200176	0.1681	37
200186	0.1503	72
200190	0.1214	27
200189	0.0703	15
200188	0.0672	19
200187	0.0644	23
200177	0.0319	7
200179	0.0286	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.50	gold quality
ganglionic eminence	UBERON:0004023	99.19	gold quality
ventricular zone	UBERON:0003053	94.90	gold quality
cauda epididymis	UBERON:0004360	91.57	gold quality
embryo	UBERON:0000922	90.55	gold quality
endothelial cell	CL:0000115	87.70	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.37	gold quality
middle temporal gyrus	UBERON:0002771	84.05	gold quality
secondary oocyte	CL:0000655	82.76	gold quality
primary visual cortex	UBERON:0002436	77.75	gold quality
occipital lobe	UBERON:0002021	74.77	gold quality
Brodmann (1909) area 10	UBERON:0013541	74.63	gold quality
Brodmann (1909) area 46	UBERON:0006483	72.98	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	72.35	gold quality
entorhinal cortex	UBERON:0002728	71.71	gold quality
corpus epididymis	UBERON:0004359	70.94	gold quality
superior frontal gyrus	UBERON:0002661	70.07	gold quality
prefrontal cortex	UBERON:0000451	69.47	gold quality
orbitofrontal cortex	UBERON:0004167	69.46	gold quality
neocortex	UBERON:0001950	68.78	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	68.34	gold quality
cerebral cortex	UBERON:0000956	68.28	gold quality
postcentral gyrus	UBERON:0002581	67.83	gold quality
frontal cortex	UBERON:0001870	67.81	gold quality
temporal lobe	UBERON:0001871	67.81	gold quality
parietal lobe	UBERON:0001872	67.65	gold quality
cerebellar vermis	UBERON:0004720	67.03	gold quality
telencephalon	UBERON:0001893	66.92	gold quality
cingulate cortex	UBERON:0003027	66.31	gold quality
anterior cingulate cortex	UBERON:0009835	66.10	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-GEOD-75140	yes	5370.50
E-GEOD-98556	yes	4363.66
E-MTAB-11121	yes	2106.66
E-HCAD-56	yes	1943.75
E-HCAD-5	yes	1400.42
E-MTAB-10485	yes	688.07
E-GEOD-93593	yes	19.79
E-ANND-3	yes	5.73
E-MTAB-8894	no	1344.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CHD8, GDNF, NR2E1

miRNA regulators (miRDB)

428 targeting DCX, 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-6867-5P	100.00	82.21	3464
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-513A-5P	100.00	69.77	2465
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-5692A	100.00	74.40	6850
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3134	100.00	66.43	777
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-9-5P	100.00	72.28	2361
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-656-3P	100.00	72.15	2788
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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• During development of the cerebral cortex DCX is expressed in both pyramidal and non-pyramidal migrating cells, as well as in Cajal-Retzius cells. (PMID:12427674)
• Missense DCX mutations may manifest as non-syndromic mental retardation with cryptogenic epilepsy in female subjects and subcortical band heterotopia (SBH) in boys. (PMID:12838518)
• Different clinical and morphological phenotypes in monozygotic twins with identical DCX mutation. (PMID:14999500)
• both mutant and wild type DCX are able to bind and bundle microtubules; however, mutants possess a decreased ability to perturb the mitotic machinery, to cause abnormal spindle orientation, and to impair mitotic progression (PMID:15045646)
• DCX maps at Xq22.3 and is caused by a homozygous mutation. It acts during corticogenesis on radial migratory pathways. (PMID:15057976)
• We analysed the human DCX regulatory sequence and confined it to a 3.5-kb fragment upstream of the ATG start codon. This fragment is sufficient and specific to drive expression of reporter genes in embryonic and adult neuronal precursors (PMID:15663475)
• doublecortin (DCX) gene as a new molecular marker of neuroblastoma cells (PMID:15714065)
• Collectively, the immunohistochemistry, Western blots and Northern blots conclusively demonstrate expression of DCX by human brain tumors. (PMID:16195916)
• Doublecortin can be regarded as specific neuronal marker only in normal developing brain, but lacks specificity in glioneuronal and glial tumours and other non-neuronal human tissues where it is expressed in a wide variety of tumours and tissues. (PMID:16520969)
• X-ray structure of a mutant of N-DCX, in which the C-terminal fragment (residues 139-147) unexpectedly shows an altered, “open” conformation (PMID:16835924)
• Our data in the mouse, identifying roles for Dcx in hippocampal and corpus callosal development, might suggest intrinsic roles for human DCX in the development of these structures. (PMID:17111359)
• Doublecortin (DCX) is one of the three genes found from Affymetrix gene chip analysis related to glioma patient survival. (PMID:17178868)
• MLPA uncovers large genomic deletions of the DCX gene in a subset of patients with SBH in whom no mutations are found after gene sequencing. Deletions of DCX are an underascertained cause of SBH. (PMID:17283321)
• Results demonstrate that DCX can be used as a marker to distinguish articular chondrocytes from other chondrocytes and to evaluate the quality of tissue engineered or regenerated cartilage in terms of their “articular” or “non-articular” nature. (PMID:17897623)
• Doublecortin is applicable for the detection of individual infiltrating glioma cells when combined with other markers. (PMID:18415660)
• X-linked lissencephaly patients with mutations in the C-DC domain tended to have a less severe lissencephaly (grade 4-5 in 58.3%) compared with those in the N-DC domain (grade 4-5 in 36.3%. (PMID:18685874)
• intragenic deletions and duplications of the DCX gene account for a significant number of patients with isolated lissencephaly sequence and subcortical band heterotopia, where no molecular defect had previously been identified. (PMID:19050731)
• Doublecortin (DCX) upregulation, correlates with better neurologic outcome in children following traumatic head injury. (PMID:19221293)
• Evidence for a role for miR-128 in neuroblastoma progression and aggressiveness through reelin and DCX expression is reported. (PMID:19713529)
• variants in doublecortin- and calmodulin kinase like 1, a gene up-regulated by BDNF, have roles in memory and general cognitive abilities (PMID:19844571)
• study describes male siblings with Lennox-Gastaut syndrome and pachygyria with a novel missense mutation in the DCX gene (PMID:20726879)
• The DCX binding on the microtubules surface indirectly stabilizes conserved tubulin-tubulin lateral contacts in the microtubules lumen, operating independently of the nucleotide bound to tubulin. (PMID:20974813)
• DCX synthesis induces apoptosis in brain tumor stem cells (BTSC) through a novel JNK1/neurabin II/DCX/PP1/caspase-3 pathway. (PMID:21477071)
• Up-regulation of doublecortin is associated with brain damage in children with acute lymphoblastic leukemia (PMID:21846577)
• Data report a negative correlation between DCX mRNA expression and white matter neuron density in schizophrenia, in contrast to a positive correlation in human development where DCX mRNA and white matter neuron density are higher earlier in life. (PMID:21966452)
• DCX binds to polymerization intermediates at growing microtubule ends, in support of a mechanism for stabilizing 13-protofilament microtubules. (PMID:22727374)
• This finding points to the possible implication of mosaic deletions in the DCX gene in unexplained forms of subcortical band heterotopia (SBH) and may allow for detection of SBH prenatally. (PMID:22833188)
• Immunoblots revealed that depressed subjects displayed increased expression of doublecortin. (PMID:23260340)
• one deleterious mutation in the DCX gene was identified in a 5-year-old girl with lissencephaly spectrum (PMID:23583063)
• DCX is dispensable for the development of new neurons in adult mice (PMID:23667508)
• coexpression of DCX and SPARC collaboratively diminished radioresistance of glioma cells. (PMID:23846421)
• We propose that DCDC2 is a tumor suppressor gene of HCC. (PMID:24034596)
• DCX-positive cells occur in a wide range of hypothalamic nuclei in humans, mice and sheep. (PMID:24288185)
• human DCX protein was expressed in human adipose stem cells, collagen II was decreased while aggrecan, matrilin 2, and GDF5 were increased during the 14-day pellet culture. (PMID:24758934)
• in utero doublecortin knockdown, but not knockout, shows a neocortical neuronal migration phenotype. (PMID:24945770)
• It was conclude that microtubule ends have two distinct features that proteins can recognize independently, namely a structural feature related to curvature and nucleotide state. (PMID:25283777)
• Results point to a critical role of doublecortin in the formation of the neuromuscular junctions. (PMID:25817838)
• From this family, we conclude that a DCX mutation causes a pleiotropic phenotype in the female even if X chromosome inactivation pattern is not skewed, and the novel missense mutation in DCX produced relatively mild dysfunction of the doublecortin protein. (PMID:25868952)
• In high-risk metastatic Neuroblastoma, TH and DCX mRNA quantification could be used for the assessment of response to treatment and for early detection of progressive disease or relapses. (PMID:26498952)
• this suggests that the microtubule-interacting doublecortin domain observed in cryo-electron micrographs is the C-terminal domain rather than the N-terminal one. (PMID:27226599)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dcx	ENSMUSG00000031285
rattus_norvegicus	Dcx	ENSRNOG00000047712
caenorhabditis_elegans		WBGENE00007007

Paralogs (6): MKNK1 (ENSG00000079277), MAPKAPK5 (ENSG00000089022), MKNK2 (ENSG00000099875), MAPKAPK3 (ENSG00000114738), CAMK4 (ENSG00000152495), MAPKAPK2 (ENSG00000162889)

Protein

Protein identifiers

Neuronal migration protein doublecortin — O43602 (reviewed: O43602)

Alternative names: Doublin, Lissencephalin-X

All UniProt accessions (9): O43602, A0A1B0GWD1, A0A7P0T9C5, A0A804CF28, A0A9L9PYE1, A0A9S7JGE9, A0A9S7N7F7, A8K340, E7EU50

UniProt curated annotations — full annotation on UniProt →

Function. Microtubule-associated protein required for initial steps of neuronal dispersion and cortex lamination during cerebral cortex development. May act by competing with the putative neuronal protein kinase DCLK1 in binding to a target protein. May in that way participate in a signaling pathway that is crucial for neuronal interaction before and during migration, possibly as part of a calcium ion-dependent signal transduction pathway. May be part with PAFAH1B1/LIS-1 of overlapping, but distinct, signaling pathways that promote neuronal migration.

Subunit / interactions. Interacts with tubulin. Interacts with USP9X.

Subcellular location. Cytoplasm. Cell projection. Neuron projection.

Tissue specificity. Highly expressed in neuronal cells of fetal brain (in the majority of cells of the cortical plate, intermediate zone and ventricular zone), but not expressed in other fetal tissues. In the adult, highly expressed in the brain frontal lobe, but very low expression in other regions of brain, and not detected in heart, placenta, lung, liver, skeletal muscles, kidney and pancreas.

Post-translational modifications. Phosphorylation by MARK1, MARK2 and PKA regulates its ability to bind microtubules. Phosphorylation at Ser-265 and Ser-297 seems to occur only in neonatal brain, the levels falling precipitously by postnatal day 21. Ubiquitinated by MDM2, leading to its degradation by the proteasome. Ubiquitinated by MDM2 and subsequent degradation leads to reduce the dendritic spine density of olfactory bulb granule cells.

Disease relevance. Lissencephaly, X-linked 1 (LISX1) [MIM:300067] A classic lissencephaly characterized by intellectual disability and seizures that are more severe in male patients. Affected boys show an abnormally thick cortex with absent or severely reduced gyri. Clinical manifestations include feeding problems, abnormal muscular tone, seizures and severe to profound psychomotor retardation. Female patients display a less severe phenotype referred to as ‘doublecortex’. The disease is caused by variants affecting the gene represented in this entry. Subcortical band heterotopia X-linked (SBHX) [MIM:300067] SBHX is a mild brain malformation of the lissencephaly spectrum. It is characterized by bilateral and symmetric plates or bands of gray matter found in the central white matter between the cortex and cerebral ventricles, cerebral convolutions usually appearing normal. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving DCX is found in lissencephaly. Translocation t(X;2)(q22.3;p25.1).

Isoforms (2)

UniProt ID	Names	Canonical?
O43602-1	1	yes
O43602-2	2

RefSeq proteins (11): NP_000546, NP_001182482, NP_001356299, NP_001356300, NP_001356301, NP_001356302, NP_001356303, NP_001397644, NP_835364, NP_835365, NP_835366 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003533	Doublecortin_dom	Domain
IPR017302	DCX_chordates	Family
IPR036572	Doublecortin_dom_sf	Homologous_superfamily

Pfam: PF03607

UniProt features (99 total): sequence variant 44, modified residue 25, strand 11, turn 6, helix 5, domain 2, region of interest 2, compositionally biased region 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
5IO9	X-RAY DIFFRACTION	1.3
5IP4	X-RAY DIFFRACTION	1.81
5IKC	X-RAY DIFFRACTION	2.06
2BQQ	X-RAY DIFFRACTION	2.2
6FNZ	X-RAY DIFFRACTION	2.23
5IOI	X-RAY DIFFRACTION	2.4
5IN7	X-RAY DIFFRACTION	2.48
6REV	ELECTRON MICROSCOPY	3.8
6RF8	ELECTRON MICROSCOPY	3.8
6RFD	ELECTRON MICROSCOPY	3.9
6RF2	ELECTRON MICROSCOPY	4.2
2XRP	ELECTRON MICROSCOPY	8.2
4ATU	ELECTRON MICROSCOPY	8.3
1MJD	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43602-F1	67.19	0.10

Antibody-complex structures (SAbDab): 2 — 5IKC, 5IP4

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 (25): 70, 74, 90, 110, 115, 265, 287, 289, 294, 297, 306, 306, 326, 326, 332, 332, 336, 339, 339, 342 …

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-447043	Neurofascin interactions

MSigDB gene sets: 410 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, YAATNRNNNYNATT_UNKNOWN, BENPORATH_ES_WITH_H3K27ME3, WWTAAGGC_UNKNOWN, NKX25_02, GOBP_NEUROGENESIS, TAL1ALPHAE47_01, LHX3_01, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, HANN_RESISTANCE_TO_BCL2_INHIBITOR_UP, MODULE_66, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, DAVICIONI_RHABDOMYOSARCOMA_PAX_FOXO1_FUSION_UP, SOX9_B1

GO Biological Process (15): neuron migration (GO:0001764), nervous system development (GO:0007399), central nervous system development (GO:0007417), axoneme assembly (GO:0035082), intracellular signal transduction (GO:0035556), retina development in camera-type eye (GO:0060041), brain development (GO:0007420), hippocampus development (GO:0021766), layer formation in cerebral cortex (GO:0021819), pyramidal neuron development (GO:0021860), central nervous system projection neuron axonogenesis (GO:0021952), cell differentiation (GO:0030154), axon extension (GO:0048675), dendrite morphogenesis (GO:0048813), regulation of postsynapse assembly (GO:0150052)

GO Molecular Function (3): microtubule binding (GO:0008017), protein kinase binding (GO:0019901), protein binding (GO:0005515)

GO Cellular Component (8): cytosol (GO:0005829), cytoskeleton (GO:0005856), microtubule (GO:0005874), microtubule associated complex (GO:0005875), neuron projection (GO:0043005), cytoplasm (GO:0005737), cell projection (GO:0042995), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
L1CAM interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
system development	2
intracellular anatomical structure	2
anatomical structure development	2
microtubule cytoskeleton	2
cell migration	1
generation of neurons	1
nervous system development	1
microtubule bundle formation	1
cellular component assembly	1
cilium assembly	1
signal transduction	1
camera-type eye development	1
central nervous system development	1
animal organ development	1
head development	1
pallium development	1
limbic system development	1
cerebral cortex radial glia-guided migration	1
anatomical structure formation involved in morphogenesis	1
pyramidal neuron differentiation	1
forebrain neuron development	1
central nervous system neuron axonogenesis	1
cellular developmental process	1
axonogenesis	1
neuron projection extension	1
dendrite development	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
regulation of synapse assembly	1
postsynapse assembly	1
regulation of postsynapse organization	1
tubulin binding	1
kinase binding	1
binding	1
cytoplasm	1
intracellular membraneless organelle	1
polymeric cytoskeletal fiber	1
protein-containing complex	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

1888 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DCX	RBFOX3	A6NFN3	885
DCX	NES	P48681	874
DCX	GFAP	P14136	857
DCX	PPP1R9B	Q96SB3	797
DCX	BDNF	P23560	778
DCX	DCDC1	P59894	761
DCX	PAFAH1B1	P43034	738
DCX	MAP2	P11137	729
DCX	CALB2	P22676	727
DCX	AIF1	P55008	721
DCX	PVALB	P20472	715
DCX	OLIG2	Q13516	705
DCX	NEUROD1	Q13562	700
DCX	CALB1	P05937	695
DCX	TH	P07101	689

IntAct

99 interactions, top by confidence:

A	B	Type	Score
ZBTB5	DCX	psi-mi:“MI:0915”(physical association)	0.670
GOLGA2	DCX	psi-mi:“MI:0915”(physical association)	0.670
DCX	IKZF1	psi-mi:“MI:0915”(physical association)	0.670
DCX	RINT1	psi-mi:“MI:0915”(physical association)	0.670
DCX	ZBTB5	psi-mi:“MI:0915”(physical association)	0.670
DCX	GOLGA2	psi-mi:“MI:0915”(physical association)	0.670
RINT1	DCX	psi-mi:“MI:0915”(physical association)	0.670
DCX	ZBTB5	psi-mi:“MI:0914”(association)	0.670
TRIM27	DCX	psi-mi:“MI:0915”(physical association)	0.560
TRIM23	DCX	psi-mi:“MI:0915”(physical association)	0.560
MEOX1	DCX	psi-mi:“MI:0915”(physical association)	0.560
DCX	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
CALCOCO2	DCX	psi-mi:“MI:0915”(physical association)	0.560
KRT40	DCX	psi-mi:“MI:0915”(physical association)	0.560
DCX	SPAG5	psi-mi:“MI:0915”(physical association)	0.560
DCX	KIFC3	psi-mi:“MI:0915”(physical association)	0.560
MID2	DCX	psi-mi:“MI:0915”(physical association)	0.560
DCX	TRIM27	psi-mi:“MI:0915”(physical association)	0.560
DCX	TRIM23	psi-mi:“MI:0915”(physical association)	0.560
DCX	MEOX1	psi-mi:“MI:0915”(physical association)	0.560
DCX	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (125): DCX (Two-hybrid), GOLGA2 (Two-hybrid), KIFC3 (Two-hybrid), MEOX1 (Two-hybrid), TRIM27 (Two-hybrid), ZBTB5 (Two-hybrid), CALCOCO2 (Two-hybrid), IKZF1 (Two-hybrid), SPAG5 (Two-hybrid), MID2 (Two-hybrid), RINT1 (Two-hybrid), KRT40 (Two-hybrid), KRTAP10-8 (Two-hybrid), DCX (Affinity Capture-MS), DCX (Affinity Capture-MS)

ESM2 similar proteins: A0A0K3AV08, A2AD83, A2CEX1, A4V8B4, A8X775, A8XFZ3, A8XU52, B6KAS6, C5DT56, F5HB62, G5EDE9, G5EDW7, G5EEC5, H2L045, O01700, O36371, O43602, O62090, O88809, P27552, P33802, Q02645, Q09994, Q10128, Q11181, Q20687, Q21341, Q22227, Q3LRZ3, Q3U5C7, Q5HZJ0, Q60JJ0, Q66624, Q6BER5, Q6E3D2, Q6E3D4, Q6ZUT3, Q71M21, Q71QF9, Q8VEB2

Diamond homologs: A8WXF6, A8X6H4, A8XW88, B3NKK1, B4GXC2, B4IMC3, B4IT27, B4NSS9, B5DK35, D2I3C6, O08875, O15075, O22932, O43602, O62305, O70150, O77708, O80902, O88809, O94547, P00517, P05131, P05132, P05383, P08413, P08414, P11275, P11798, P12370, P13234, P15791, P17612, P21137, P22612, P22694, P25321, P25323, P27791, P28583, P28652

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
GSK3B	“up-regulates activity”	DCX	phosphorylation
CDK5/CDK5R1	unknown	DCX	phosphorylation
CDK5/CDK5R1	“up-regulates activity”	DCX	phosphorylation
MAPK8	“up-regulates activity”	DCX	phosphorylation
CHD8	“down-regulates quantity”	DCX	“transcriptional regulation”
GDNF	“down-regulates quantity by repression”	DCX	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 71 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
AURKA Activation by TPX2	5	16.6×	8e-04
Regulation of PLK1 Activity at G2/M Transition	5	13.8×	2e-03
Cell Cycle	8	6.3×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	116
Likely pathogenic	41
Uncertain significance	101
Likely benign	32
Benign	12

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
11599	NM_001195553.2(DCX):c.373T>C (p.Tyr125His)	Pathogenic
11601	NM_001195553.2(DCX):c.176G>T (p.Arg59Leu)	Pathogenic
11602	NM_001195553.2(DCX):c.608C>G (p.Thr203Arg)	Pathogenic
11604	NM_001195553.2(DCX):c.34_35dup (p.Asp12fs)	Pathogenic
11606	NM_001195553.2(DCX):c.691_692del (p.Leu231fs)	Pathogenic
11607	NM_001195553.2(DCX):c.233G>A (p.Arg78His)	Pathogenic
11608	NM_001195553.2(DCX):c.265C>G (p.Arg89Gly)	Pathogenic
11609	NM_001195553.2(DCX):c.587G>A (p.Arg196His)	Pathogenic
11610	NM_001195553.2(DCX):c.211G>T (p.Ala71Ser)	Pathogenic
1176951	NM_001195553.2(DCX):c.365-1G>T	Pathogenic
1180597	NM_001195553.2(DCX):c.240dup (p.Asp81Ter)	Pathogenic
1210701	NM_001195553.2(DCX):c.478dup (p.Gln160fs)	Pathogenic
1285488	NM_001195553.2(DCX):c.478del (p.Gln160fs)	Pathogenic
1320092	NM_001195553.2(DCX):c.304C>A (p.Arg102Ser)	Pathogenic
1342885	NM_001195553.2(DCX):c.628del (p.Val210fs)	Pathogenic
1413015	NM_001195553.2(DCX):c.705+1G>A	Pathogenic
1446866	NM_001195553.2(DCX):c.414_415insG (p.Thr139fs)	Pathogenic
1457133	NM_001195553.2(DCX):c.37_38del (p.Lys13fs)	Pathogenic
153209	GRCh38/hg38 Xq23(chrX:111318320-111348178)x3	Pathogenic
158424	NM_001195553.2(DCX):c.1045-2A>G	Pathogenic
158425	NM_001195553.2(DCX):c.115C>T (p.Arg39Ter)	Pathogenic
158426	NM_001195553.2(DCX):c.124del (p.Thr42fs)	Pathogenic
158427	NM_001195553.2(DCX):c.128T>C (p.Leu43Ser)	Pathogenic
158428	NM_001195553.2(DCX):c.130C>T (p.Gln44Ter)	Pathogenic
158429	NM_001195553.2(DCX):c.150G>T (p.Lys50Asn)	Pathogenic
158430	NM_001195553.2(DCX):c.151_154del (p.Lys51fs)	Pathogenic
158434	NM_001195553.2(DCX):c.182G>A (p.Gly61Glu)	Pathogenic
158439	NM_001195553.2(DCX):c.210C>A (p.Tyr70Ter)	Pathogenic
158440	NM_001195553.2(DCX):c.218C>T (p.Ser73Phe)	Pathogenic
158442	NM_001195553.2(DCX):c.232C>T (p.Arg78Cys)	Pathogenic

SpliceAI

1287 predictions. Top by Δscore:

Variant	Effect	Δscore
X:111331038:CATT:C	acceptor_gain	1.0000
X:111331039:ATTC:A	acceptor_loss	1.0000
X:111331040:TT:T	acceptor_gain	1.0000
X:111331040:TTC:T	acceptor_loss	1.0000
X:111331041:TC:T	acceptor_loss	1.0000
X:111331042:C:CC	acceptor_gain	1.0000
X:111331042:C:CG	acceptor_loss	1.0000
X:111333045:GCTTA:G	donor_loss	1.0000
X:111333046:CTTA:C	donor_loss	1.0000
X:111333047:TTACC:T	donor_loss	1.0000
X:111333048:TACCA:T	donor_loss	1.0000
X:111333049:A:AC	donor_gain	1.0000
X:111333049:A:C	donor_loss	1.0000
X:111333050:C:CA	donor_loss	1.0000
X:111333050:C:CC	donor_gain	1.0000
X:111333151:TACC:T	acceptor_loss	1.0000
X:111333154:C:A	acceptor_loss	1.0000
X:111333155:T:A	acceptor_loss	1.0000
X:111400986:CTAC:C	donor_loss	1.0000
X:111400988:A:AC	donor_gain	1.0000
X:111400989:C:CT	donor_gain	1.0000
X:111400989:CCTG:C	donor_gain	1.0000
X:111401328:CCC:C	acceptor_gain	1.0000
X:111401329:CC:C	acceptor_gain	1.0000
X:111401329:CCC:C	acceptor_gain	1.0000
X:111401329:CCCTA:C	acceptor_loss	1.0000
X:111401330:CC:C	acceptor_gain	1.0000
X:111401330:CCTAA:C	acceptor_loss	1.0000
X:111401331:C:A	acceptor_loss	1.0000
X:111401331:C:CC	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000020371 (X:111373183 C>A), RS1000068584 (X:111330621 A>C), RS1000072625 (X:111373685 C>T), RS1000082991 (X:111381178 A>T), RS1000196766 (X:111412004 GA>G), RS1000199265 (X:111331432 T>C,G), RS1000224578 (X:111303235 C>A,T), RS1000261523 (X:111370558 G>A,C,T), RS1000371119 (X:111382829 G>A), RS1000378886 (X:111293310 C>A,T), RS1000430571 (X:111327155 G>T), RS1000471422 (X:111360408 T>C,G), RS1000550491 (X:111305577 C>A,T), RS1000561202 (X:111365948 C>T), RS1000631052 (X:111363990 G>A,C)

Disease associations

OMIM: gene MIM:300121 | disease phenotypes: MIM:300067, MIM:607432, MIM:308350, MIM:230000

GenCC curated gene-disease

Disease	Classification	Inheritance
lissencephaly spectrum disorders	Definitive	X-linked
lissencephaly type 1 due to doublecortin gene mutation	Definitive	X-linked
subcortical band heterotopia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
lissencephaly spectrum disorders	Definitive	XL

Mondo (8): lissencephaly type 1 due to doublecortin gene mutation (MONDO:0010239), neurodevelopmental disorder (MONDO:0700092), congenital nervous system disorder (MONDO:0002320), lissencephaly spectrum disorders (MONDO:0018838), subcortical band heterotopia (MONDO:0020491), intellectual disability (MONDO:0001071), genetic developmental and epileptic encephalopathy (MONDO:0100062), fucosidosis (MONDO:0009254)

Orphanet (5): Lissencephaly type 1 due to doublecortin gene mutation (Orphanet:2148), Lissencephaly (Orphanet:48471), Subcortical band heterotopia (Orphanet:99796), Fucosidosis (Orphanet:349), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

46 total (30 of 46 shown, HPO-id order):

HPO	Term
HP:0000054	Micropenis
HP:0000639	Nystagmus
HP:0000708	Atypical behavior
HP:0000713	Agitation
HP:0000729	Autistic behavior
HP:0000737	Irritability
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001274	Agenesis of corpus callosum
HP:0001302	Pachygyria
HP:0001339	Lissencephaly
HP:0001371	Flexion contracture
HP:0001417	X-linked inheritance
HP:0001522	Death in infancy
HP:0002015	Dysphagia
HP:0002079	Hypoplasia of the corpus callosum
HP:0002197	Generalized-onset seizure
HP:0002282	Gray matter heterotopia
HP:0002339	Abnormal caudate nucleus morphology
HP:0002463	Language impairment
HP:0002521	Hypsarrhythmia
HP:0002650	Scoliosis
HP:0002835	Aspiration
HP:0003593	Infantile onset
HP:0003808	Abnormal muscle tone
HP:0003829	Typified by incomplete penetrance

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D005645	Fucosidosis	C10.228.140.163.100.435.295; C16.320.565.189.435.295; C16.320.565.202.303; C16.320.565.595.554.295; C18.452.132.100.435.295; C18.452.648.189.435.295; C18.452.648.202.303; C18.452.648.595.554.295
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D054082	Lissencephaly	C10.500.507.450.499; C16.131.666.507.450.499
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067034 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.27	Kd	536.4	nM	CHEMBL3752910
6.27	ED50	536.4	nM	CHEMBL3752910
5.03	Kd	9398	nM	CHEMBL5653589
5.03	ED50	9398	nM	CHEMBL5653589

PubChem BioAssay actives

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

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148206: Binding affinity to human DCX incubated for 45 mins by Kinobead based pull down assay	kd	0.5364	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148206: Binding affinity to human DCX incubated for 45 mins by Kinobead based pull down assay	kd	9.3981	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, affects cotreatment, increases expression	9
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	3
methylmercuric chloride	decreases expression	2
sodium arsenite	affects cotreatment, decreases expression, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
LDN 193189	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
lead acetate	decreases expression, affects cotreatment	1
ascorbate-2-phosphate	affects cotreatment, decreases expression, affects binding	1
trichostatin A	increases expression	1
bis(2,3,3,3-tetrachloropropyl) ether	affects cotreatment, increases expression	1
diethyl phosphate	affects cotreatment, increases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
Chir 99021	decreases expression, affects cotreatment, increases expression, affects binding	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
thifluzamide	decreases expression	1
pyrachlostrobin	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
XAV939	affects binding, affects cotreatment, decreases expression	1
picoxystrobin	decreases expression	1
3-(4-pyridyl)-1H-indole	increases expression, affects cotreatment	1
Aripiprazole	decreases expression	1
Resveratrol	increases expression	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
CHEMBL5651248	Binding	Binding affinity to human DCX incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D1S4	Abcam U-87MG DCX KO	Cancer cell line	Male
CVCL_D4ZQ	SDQLCHi067-A	Induced pluripotent stem cell	Female
CVCL_E0Z4	Ubigene MG-63 DCX KO	Cancer cell line	Male
CVCL_RG03	PFIZi027-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice