DLG1

Summary

DLG1 (discs large MAGUK scaffold protein 1, HGNC:2900) is a protein-coding gene on chromosome 3q29, encoding Disks large homolog 1 (Q12959). Essential multidomain scaffolding protein required for normal development.

This gene encodes a multi-domain scaffolding protein that is required for normal development. This protein may have a role in septate junction formation, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation. A multitude of transcript variants deriving from alternative splicing and the use of multiple alternate promoter have been observed, including some splice variants that may be specific to brain and other tissues. An upstream uORF may regulate translation at some splice variants of this gene.

Source: NCBI Gene 1739 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Brugada syndrome (Limited, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 172 total — 3 pathogenic
• Phenotypes (HPO): 21
• MANE Select transcript: NM_001366207

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2900
Approved symbol	DLG1
Name	discs large MAGUK scaffold protein 1
Location	3q29
Locus type	gene with protein product
Status	Approved
Aliases	SAP97, SAP-97, hdlg, DLGH1, dJ1061C18.1.1
Ensembl gene	ENSG00000075711
Ensembl biotype	protein_coding
OMIM	601014
Entrez	1739

Gene structure

Transcript identifiers

Ensembl transcripts: 102 — 77 protein_coding, 15 nonsense_mediated_decay, 6 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000346964, ENST00000357674, ENST00000392380, ENST00000392381, ENST00000392382, ENST00000412364, ENST00000419227, ENST00000419354, ENST00000419553, ENST00000422288, ENST00000434148, ENST00000436682, ENST00000443183, ENST00000447466, ENST00000448528, ENST00000450955, ENST00000452595, ENST00000453607, ENST00000456699, ENST00000469073, ENST00000469371, ENST00000470629, ENST00000471733, ENST00000475394, ENST00000477312, ENST00000485409, ENST00000486877, ENST00000493937, ENST00000653331, ENST00000653583, ENST00000653795, ENST00000654733, ENST00000654737, ENST00000655488, ENST00000656087, ENST00000656428, ENST00000656944, ENST00000657098, ENST00000657381, ENST00000658155, ENST00000658701, ENST00000659221, ENST00000659716, ENST00000660237, ENST00000660432, ENST00000660553, ENST00000660898, ENST00000661013, ENST00000661229, ENST00000661336, ENST00000661440, ENST00000661453, ENST00000661808, ENST00000662727, ENST00000663148, ENST00000664564, ENST00000664991, ENST00000665728, ENST00000666007, ENST00000667104, ENST00000667157, ENST00000667971, ENST00000668578, ENST00000669332, ENST00000669565, ENST00000669714, ENST00000670366, ENST00000670455, ENST00000670935, ENST00000671185, ENST00000671246, ENST00000887907, ENST00000887908, ENST00000887909, ENST00000887910, ENST00000887911, ENST00000918289, ENST00000918290, ENST00000918291, ENST00000918292, ENST00000918293, ENST00000918294, ENST00000918295, ENST00000918296, ENST00000918297, ENST00000918298, ENST00000918299, ENST00000918300, ENST00000918301, ENST00000948483, ENST00000948485, ENST00000948486, ENST00000948487, ENST00000948488, ENST00000948489, ENST00000948490, ENST00000948491, ENST00000948492, ENST00000948493, ENST00000948494, ENST00000948495, ENST00000948496

RefSeq mRNA: 27 — MANE Select: NM_001366207 NM_001098424, NM_001204386, NM_001204387, NM_001204388, NM_001290983, NM_001363865, NM_001366203, NM_001366204, NM_001366205, NM_001366206, NM_001366207, NM_001366208, NM_001366209, NM_001366210, NM_001366211, NM_001366212, NM_001366213, NM_001366214, NM_001366215, NM_001366216, NM_001366217, NM_001366218, NM_001366219, NM_001366220, NM_001366221, NM_001366222, NM_004087

CCDS: CCDS3327, CCDS43194, CCDS56300, CCDS56301, CCDS75072, CCDS87192, CCDS93447, CCDS93448, CCDS93449, CCDS93450, CCDS93451, CCDS93452, CCDS93453, CCDS93454

Canonical transcript exons

ENST00000667157 — 25 exons

Exon	Start	End
ENSE00001232979	197042560	197044729
ENSE00003459007	197296346	197296477
ENSE00003477780	197140140	197140264
ENSE00003481155	197069219	197069260
ENSE00003487283	197119410	197119530
ENSE00003512997	197065708	197065809
ENSE00003514843	197090912	197091026
ENSE00003518986	197142718	197142768
ENSE00003546008	197051577	197051668
ENSE00003555384	197085580	197085756
ENSE00003563675	197104903	197105005
ENSE00003572262	197194425	197194589
ENSE00003572428	197059889	197059998
ENSE00003583505	197136542	197136678
ENSE00003596024	197115927	197116083
ENSE00003616517	197066704	197066754
ENSE00003622614	197081051	197081117
ENSE00003631842	197297186	197297235
ENSE00003645024	197138222	197138391
ENSE00003647447	197076586	197076685
ENSE00003673684	197065276	197065448
ENSE00003676901	197130527	197130671
ENSE00003788504	197149743	197149796
ENSE00003789567	197282679	197282845
ENSE00003863576	197298536	197298612

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.1390 / max 1937.7379, expressed in 1814 samples.

FANTOM5 promoters (25 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46432	15.6147	1738
46431	4.7157	1560
46423	3.5375	692
46430	2.7597	1288
46426	1.7893	653
46429	1.3631	758
46411	0.7144	104
46435	0.4198	250
46414	0.3176	72
46408	0.2857	73

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.06	gold quality
esophagus squamous epithelium	UBERON:0006920	97.92	gold quality
corpus callosum	UBERON:0002336	97.80	gold quality
tongue squamous epithelium	UBERON:0006919	97.63	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.55	gold quality
inferior olivary complex	UBERON:0002127	97.28	gold quality
inferior vagus X ganglion	UBERON:0005363	97.15	gold quality
squamous epithelium	UBERON:0006914	97.10	gold quality
epithelium of esophagus	UBERON:0001976	97.07	gold quality
subthalamic nucleus	UBERON:0001906	96.94	gold quality
colonic epithelium	UBERON:0000397	96.90	gold quality
hair follicle	UBERON:0002073	96.67	gold quality
pigmented layer of retina	UBERON:0001782	96.63	gold quality
lateral globus pallidus	UBERON:0002476	96.63	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.63	gold quality
postcentral gyrus	UBERON:0002581	96.54	gold quality
tibia	UBERON:0000979	96.53	gold quality
medulla oblongata	UBERON:0001896	96.46	gold quality
choroid plexus epithelium	UBERON:0003911	96.44	gold quality
parietal lobe	UBERON:0001872	96.27	gold quality
entorhinal cortex	UBERON:0002728	96.25	gold quality
globus pallidus	UBERON:0001875	96.13	gold quality
gingival epithelium	UBERON:0001949	96.13	gold quality
superior vestibular nucleus	UBERON:0007227	96.13	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.12	gold quality
medial globus pallidus	UBERON:0002477	95.89	gold quality
CA1 field of hippocampus	UBERON:0003881	95.86	gold quality
secondary oocyte	CL:0000655	95.81	gold quality
middle temporal gyrus	UBERON:0002771	95.78	gold quality
superior frontal gyrus	UBERON:0002661	95.65	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	82.90
E-HCAD-25	yes	54.10
E-ANND-3	yes	6.28
E-MTAB-9689	no	547.99

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

150 targeting DLG1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-651-3P	99.94	73.48	5177

Literature-anchored findings (GeneRIF, showing 40)

• PDZ2 domain binds TOPK/PBK, a novel mitotic kinase. (PMID:10779557)
• We identify the functions of the two alternatively spliced regions. The N-terminal alternatively spliced region is capable of binding several SH3 domains and also moderates the level of protein oligomerization. (PMID:11723125)
• results suggest that the SH3, HOOK and GK domains of hDLG are important for its cytoplasmic localization (PMID:12081647)
• changes in expression in high-grade premalignant cervical neoplasias; data suggest that loss of hDlg at sites of intercellular contact may be an important step in the development of epithelial cancers (PMID:12419826)
• SAP97 is an intracellular binding partner of TACE and may have a role in the regulation of TACE shedding activity (PMID:12668732)
• alternatively spliced I3 insertion plays a critical role in recruiting hDlg to the lateral membrane in epithelial cells via its interaction with protein 4.1R (PMID:12807908)
• Upon hyperphosphorylation, hDlg interacts with the beta-TrCP ubiquitin ligase receptor through a DSGLPS motif, and consequently, overexpression of beta-TrCP enhances ubiquitination of Dlg protein and decreases its stability. (PMID:12902344)
• multiple isoforms of SAP97 were identifed in human heart atrium specimens; isoforms were found to co-immunoprecipiate with hKv1.5; isoforms were found to have distinct effect on hKv1.5 current and spatial channel organization (PMID:12970345)
• hDlg may be a determinant in E-cadherin-mediated adhesion and signaling in mammalian epithelial cells (PMID:14699157)
• Dlg downregulation and/or alterations in its localization may contribute to transformation and may explain some of the characteristics of cervix neoplasms. (PMID:15221964)
• hDlg stabilizes HTLV-1 envelope glycoproteins at the virological synapse formed between infected and target cells, hence assisting the cell-to-cell transmission of the virus (PMID:15286176)
• Delta1 recruits Dlg1 at cell-cell contacts and regulates cell migration. (PMID:15485825)
• AKAP79/150 coordinates different enzyme combinations to modulate the activity of two distinct neuronal ion channels: AMPA-type glutamate receptors and M-type potassium channels (PMID:16228013)
• specific inhibition of kinase C by Calphostin C eliminated the increase in wild-type potassium channel protein Kv1.5 currents associated with SAP97 overexpression suggesting a role for this kinase in the response (PMID:16466689)
• Down-regulation of DLG1 is associated with colon cancer progression (PMID:16619250)
• Crystal structure of the second PDZ domain of SAP97 in complex. (PMID:17069616)
• Dlgh1 also regulates smooth muscle orientation, and human DLG1 mutations may contribute to hereditary forms of hydronephrosis (PMID:17172448)
• MPP7 targets to the lateral surface of epithelial cells via its L27N domain, through an interaction with Dlg1. (PMID:17332497)
• The different hDlg isoforms play distinct roles at various stages of epithelial differentiation. (PMID:17574238)
• Binding of the SH3-I3-GUK module of hDlg to GAKIN activates the microtubule-stimulated ATPase activity of GAKIN by approximately 10-fold. We propose: the cargo-mediated regulation of motor activity is a general paradigm for the activation of kinesins. (PMID:17696365)
• Isothermal titration calorimetry with a series of peptides showed that HPV-18 E6 bound hDlg PDZ2 about 5-fold stronger than HPV-16 E6; the binding was disabled by phosphorylation at Thr156. (PMID:17713926)
• MARCH2 is co-localized with DLG1 at sites of cell-cell contact. (PMID:17980554)
• SAP97 regulates the K(+) current in cardiac myocytes by retaining and immobilizing Kv1.5 subunits in the plasma membrane. (PMID:18245566)
• Dlg1, through the interaction with GLUT1 and Env, plays a positive role in the syncytium formation induced by HTLV-1. (PMID:18461433)
• The present findings suggest that the SAP97 gene may be a susceptibility factor in male schizophrenics and that the modification of the glutamate receptors-SAP97 signaling pathway could be involved in the disease pathophysiology. (PMID:18665322)
• Data suggest a role for Snail transcription factors in the control of DLG1 expression and provide a basis for understanding the transcriptional regulation of DLG1 (PMID:18725271)
• Results suggest that human discs large and GAKIN play functional roles in the maintenance of midbody architecture during cytokinesis. (PMID:18760273)
• DLG1 participates in the control of TGFalpha bioavailability through its dynamic interaction with the growth factor precursor and TACE. (PMID:18930083)
• Muscarinic-induced recruitment of plasma membrane Ca2+-ATPase involves PSD-95/Dlg/Zo-1-mediated interactions. (PMID:19017653)
• These findings establish phosphorylation events by CDKs 1 and 2 as key regulators of Discs Large 1 localisation and function. (PMID:19066288)
• SAP97 is a major partner for surface expression and CaMKII-dependent regulation of cardiac Kv4.2 and kv4.3 channels. (PMID:19213956)
• nuclear forms of Dlg phosphorylated on its CDK phospho-acceptor sites has enhanced susceptibility to E6-induced degradation (PMID:19307009)
• Net1 requires interaction with PDZ domain proteins, such as Dlg1, to protect it from proteasome-mediated degradation and to maximally stimulate RhoA and that this interaction is regulated by cell-cell contact. (PMID:19586902)
• analysis of the crystal structure of a small protein domain, SAP97 PDZ2 I342W C378A, and its folding pathway (PMID:20356847)
• These results uncover a crucial function for ezrin, Dlg1 and microtubules in the organization of the immune synapse and TCR signal down-regulation. (PMID:20551903)
• In response to hyperosmotic stress, p38 also regulates formation of complexes between hDlg and PSF. (PMID:20605917)
• these results reveal a previously unreported pathway for hDlg phosphorylation in mitosis and show that ERK5 pathway mediates hDlg cell cycle dependent phosphorylation. (PMID:20643107)
• The Dlg1-MPP7-Mals3 heterotrimer consists of 2 pairs of heterodimeric L27 domains. These 2 dimers are asymmetric due to the large difference between the N- and C-terminal tandem L27 domain of MPP7. (PMID:20702775)
• These findings not only indicate SAP97 as a point of convergence between amyloid cascade and synaptic failure in AD, but also allow a different interpretation of AD which can be now perceived as synaptic trafficking defect pathology. (PMID:20980075)
• The Dlg1 interacts with dynein via the scaffolding protein GKAP and together, Dlg1, GKAP, and dynein control microtubule dynamics and organization near the cell cortex and promote centrosome positioning. (PMID:21041448)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dlg1b	ENSDARG00000102216
mus_musculus	Dlg1	ENSMUSG00000022770
rattus_norvegicus	Dlg1	ENSRNOG00000038597

Paralogs (3): DLG3 (ENSG00000082458), DLG4 (ENSG00000132535), DLG2 (ENSG00000150672)

Protein

Protein identifiers

Disks large homolog 1 — Q12959 (reviewed: Q12959)

Alternative names: Synapse-associated protein 97, hDlg

All UniProt accessions (38): Q12959, A0A0C4DFT3, A0A590UJ08, A0A590UJ18, A0A590UJ25, A0A590UJ29, A0A590UJ64, A0A590UJ68, A0A590UJ81, A0A590UJ86, A0A590UJ95, A0A590UJC5, A0A590UJD9, A0A590UJE6, A0A590UJL2, A0A590UJR4, A0A590UJR5, A0A590UJS9, A0A590UJX2, A0A590UJZ4, A0A590UK02, A0A590UK13, A0A590UK31, A0A590UK48, A0A590UK52, A0A590UK70, A0A590UK81, A0A590UKA8, A8MUT6, B4E2H8, C9IYP1, C9J110, C9JCP6, C9JN61, C9JUA9, E7EQD7, F2Z2L0, H7C166

UniProt curated annotations — full annotation on UniProt →

Function. Essential multidomain scaffolding protein required for normal development. Recruits channels, receptors and signaling molecules to discrete plasma membrane domains in polarized cells. Promotes epithelial cell layer barrier function via maintaining cell-cell adhesion. May also play a role in adherens junction assembly, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation. Regulates the excitability of cardiac myocytes by modulating the functional expression of Kv4 channels. Functional regulator of Kv1.5 channel. During long-term depression in hippocampal neurons, it recruits ADAM10 to the plasma membrane.

Subunit / interactions. Homotetramer. Interacts (via guanylate kinase-like domain) with DLGAP1, DLGAP2, DLGAP3, DLGAP4 and MAP1A. Interacts (via guanylate kinase-like domain) with KIF13B. May interact with HTR2A. Interacts (via PDZ domains) with GRIA1. Interacts (via PDZ domains) with GRIN2A. Interacts (via PDZ domains) with KCND2 and KCND3. Interacts (via PDZ domains) with KCNA1, KCNA2, KCNA3 and KCNA4. Interacts (via PDZ domains) with ADGRA3. Interacts with KCNF1. Interacts with CAMK2. Interacts with cytoskeleton-associated protein EPB41. Interacts with cytoskeleton-associated protein EZR. Found in a complex with KCNA5 and CAV3. Found in a complex with APC and CTNNB1. Interacts (via PDZ domains) with APC. Interacts with CDH1 through binding to PIK3R1. Forms multiprotein complexes with CASK, LIN7A, LIN7B, LIN7C, APBA1, and KCNJ12. Interacts with TOPK. Forms a tripartite complex composed of DLG1, MPP7 and LIN7 (LIN7A or LIN7C). May interact with TJAP1. Interacts with PTEN. Interacts with FRMPD4 (via C-terminus). Interacts with LRFN1, LRFN2 and LRFN4. Interacts with SFPQ. Interacts (via PDZ domains) with ADGRA2 (via PDZ-binding motif). Interacts with ADAM10; this interaction recruits ADAM10 to the cell membrane during long-term depression in hippocampal neurons. Interacts with DGKI (via PDZ-binding motif). Interacts (via PDZ domains) with MARCHF2 (via PDZ domain); the interaction leads to DLG1 ubiquitination and degradation. Interacts (via N-terminus) with MPP3; this interaction connects CADM1 with DLG1 and links CADM1 with the regulatory subunit of phosphoinositide-3-kinase (PI3K) by forming a multiprotein complex and participates in cell spreading. (Microbial infection) Interacts with HTLV-1 protein Tax. (Microbial infection) Interacts (via PDZ domains 1 and 2) with influenza A virus protein NS1; the interaction results in the translocation of DLG1 from the cell membrane to perinuclear puncta. Acts as a scaffold protein to facilitate the interaction between LIN7C and influenza A virus protein NS1; the interaction facilitates translocation of LIN7C to cytoplasmic puncta. (Microbial infection) Interacts with human papillomavirus 18/HPV-18 protein E6.

Subcellular location. Cell membrane. Basolateral cell membrane. Endoplasmic reticulum membrane. Postsynaptic density. Synapse. Sarcolemma. Apical cell membrane. Cell junction. Cytoplasm.

Tissue specificity. Abundantly expressed in atrial myocardium (at protein level). Expressed in lung fibroblasts, cervical epithelial and B-cells (at protein level). Expressed in the brain (at protein level). Widely expressed, with isoforms displaying different expression profiles.

Post-translational modifications. Phosphorylated by MAPK12. Phosphorylation of Ser-232 regulates association with GRIN2A. Ubiquitinated; by MARCHF2 which results in its degradation.

Domain organisation. The alternatively spliced domain I3 corresponding to amino acids (636-669) of isoform 4 is an EPB41 binding site mediating association to membranes in polarized and non-polarized cells. The PDZ domains may also mediate association to membranes by binding to EPB41 and ADGRA2 together with the L27 domain that binds CASK and DLG2. The L27 domain may regulate DLG1 self-association. The N-terminal alternatively spliced region is capable of binding several SH3 domains and also moderates the level of protein oligomerization.

Similarity. Belongs to the MAGUK family.

Isoforms (9)

UniProt ID	Names	Canonical?
Q12959-1	1	yes
Q12959-2	2
Q12959-3	3
Q12959-4	4
Q12959-5	5
Q12959-6	6
Q12959-7	7
Q12959-8	8
Q12959-9	9

RefSeq proteins (27): NP_001091894, NP_001191315, NP_001191316, NP_001191317, NP_001277912, NP_001350794, NP_001353132, NP_001353133, NP_001353134, NP_001353135, NP_001353136, NP_001353137, NP_001353138, NP_001353139, NP_001353140, NP_001353141, NP_001353142, NP_001353143, NP_001353144, NP_001353145, NP_001353146, NP_001353147, NP_001353148, NP_001353149, NP_001353150, NP_001353151, NP_004078 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR001478	PDZ	Domain
IPR004172	L27_dom	Domain
IPR008144	Guanylate_kin-like_dom	Domain
IPR008145	GK/Ca_channel_bsu	Domain
IPR015143	L27_1	Domain
IPR016313	DLG1-like	Family
IPR019583	DLG1-4_PDZ_assoc	Domain
IPR019590	DLG1_PEST_dom	Domain
IPR020590	Guanylate_kinase_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036892	L27_dom_sf	Homologous_superfamily
IPR050614	Synaptic_Scaffolding_LAP-MAGUK	Family

Pfam: PF00018, PF00595, PF00625, PF09058, PF10600, PF10608

Enzyme classification (BRENDA):

• EC 2.7.4.8 — guanylate kinase (BRENDA: 22 organisms, 121 substrates, 63 inhibitors, 85 Km, 28 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
GMP	0.002–1.8	39
DGMP	0.01–0.4	15
ATP	0.12–1	6
MGATP2-	0.2–0.45	5
8-AZAGUANOSINE 5’-MONOPHOSPHATE	0.013–0.091	3
(R)-GANCICLOVIR PHOSPHONATE	0.052	1
6-THIOGUANOSINE 5’-MONOPHOSPHATE	2.1	1
9-(5-PHOSPHONOPENTYL)GUANINE	0.25	1
ADENOSINE TRIPHOSPHATE	23.6	1
CO2+	1.25	1
GANCICLOVIR MONOPHOSPHATE	0.047	1
GDP	0.097	1
GUANOSINE MONOPHOSPHATE	0.0051	1
MG2+	1	1
MGADP-	0.017	1

UniProt features (92 total): strand 26, helix 19, modified residue 17, splice variant 8, domain 6, turn 4, sequence variant 3, sequence conflict 3, region of interest 3, chain 1, compositionally biased region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
7PC3	X-RAY DIFFRACTION	1.95
2X7Z	X-RAY DIFFRACTION	2
4G69	X-RAY DIFFRACTION	2
8CN1	X-RAY DIFFRACTION	2.09
3RL8	X-RAY DIFFRACTION	2.2
3W9Y	X-RAY DIFFRACTION	2.2
3RL7	X-RAY DIFFRACTION	2.3
4AMH	X-RAY DIFFRACTION	2.3
8CN3	X-RAY DIFFRACTION	2.71
1PDR	X-RAY DIFFRACTION	2.8
3LRA	X-RAY DIFFRACTION	2.95
2M3M	SOLUTION NMR
2OQS	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12959-F1	73.76	0.48

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 (17): 115, 122, 138, 158, 232, 399, 568, 573, 575, 579, 598, 619, 684, 687, 834, 709, 676

Mutagenesis-validated functional residues (1):

Position	Phenotype
38–40	loss of membrane association and dlg2-binding.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-399719	Trafficking of AMPA receptors
R-HSA-438066	Unblocking of NMDA receptors, glutamate binding and activation
R-HSA-442982	Ras activation upon Ca2+ influx through NMDA receptor
R-HSA-447038	NrCAM interactions
R-HSA-451308	Activation of Ca-permeable Kainate Receptor
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-8849932	Synaptic adhesion-like molecules
R-HSA-9609736	Assembly and cell surface presentation of NMDA receptors
R-HSA-9617324	Negative regulation of NMDA receptor-mediated neuronal transmission
R-HSA-9620244	Long-term potentiation

MSigDB gene sets: 626 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GCM_MAP4K4, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_IONOTROPIC_ACTIVITY_OF_KAINATE_RECEPTORS, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_MUSCLE_TISSUE_DEVELOPMENT

GO Biological Process (64): negative regulation of transcription by RNA polymerase II (GO:0000122), branching involved in ureteric bud morphogenesis (GO:0001658), immunological synapse formation (GO:0001771), endothelial cell proliferation (GO:0001935), lens development in camera-type eye (GO:0002088), actin filament organization (GO:0007015), establishment or maintenance of cell polarity (GO:0007163), chemical synaptic transmission (GO:0007268), nervous system development (GO:0007399), positive regulation of cell population proliferation (GO:0008284), regulation of cell shape (GO:0008360), actin filament polymerization (GO:0030041), peristalsis (GO:0030432), positive regulation of actin filament polymerization (GO:0030838), cortical actin cytoskeleton organization (GO:0030866), astral microtubule organization (GO:0030953), protein-containing complex localization (GO:0031503), membrane raft organization (GO:0031579), regulation of myelination (GO:0031641), protein localization to synapse (GO:0035418), T cell proliferation (GO:0042098), negative regulation of T cell proliferation (GO:0042130), regulation of membrane potential (GO:0042391), amyloid precursor protein metabolic process (GO:0042982), receptor clustering (GO:0043113), positive regulation of potassium ion transport (GO:0043268), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), cortical microtubule organization (GO:0043622), establishment or maintenance of epithelial cell apical/basal polarity (GO:0045197), reproductive structure development (GO:0048608), embryonic skeletal system morphogenesis (GO:0048704), smooth muscle tissue development (GO:0048745), negative regulation of epithelial cell proliferation (GO:0050680), establishment of centrosome localization (GO:0051660), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), hard palate development (GO:0060022), negative regulation of ERK1 and ERK2 cascade (GO:0070373), bicellular tight junction assembly (GO:0070830), protein localization to plasma membrane (GO:0072659), receptor localization to synapse (GO:0097120)

GO Molecular Function (15): GMP kinase activity (GO:0004385), phosphoprotein phosphatase activity (GO:0004721), cytoskeletal protein binding (GO:0008092), potassium channel regulator activity (GO:0015459), kinase binding (GO:0019900), protein kinase binding (GO:0019901), phosphatase binding (GO:0019902), ionotropic glutamate receptor binding (GO:0035255), transmembrane transporter binding (GO:0044325), cadherin binding (GO:0045296), molecular adaptor activity (GO:0060090), L27 domain binding (GO:0097016), structural constituent of postsynaptic density (GO:0098919), protein binding (GO:0005515), enzyme binding (GO:0019899)

GO Cellular Component (37): immunological synapse (GO:0001772), basement membrane (GO:0005604), nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), microtubule (GO:0005874), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), adherens junction (GO:0005912), bicellular tight junction (GO:0005923), cytoplasmic side of plasma membrane (GO:0009898), intercalated disc (GO:0014704), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), lateral plasma membrane (GO:0016328), cell junction (GO:0030054), cell projection membrane (GO:0031253), neuromuscular junction (GO:0031594), node of Ranvier (GO:0033268), myelin sheath abaxonal region (GO:0035748), sarcolemma (GO:0042383), neuron projection (GO:0043005), lateral loop (GO:0043219), membrane raft (GO:0045121), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), MPP7-DLG1-LIN7 complex (GO:0097025), synaptic membrane (GO:0097060), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), postsynaptic density (GO:0014069), membrane (GO:0016020), synapse (GO:0045202), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Activation of NMDA receptors and postsynaptic events	3
Glutamate binding, activation of AMPA receptors and synaptic plasticity	1
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1
L1CAM interactions	1
Ionotropic activity of kainate receptors	1
MAPK1/MAPK3 signaling	1
Protein-protein interactions at synapses	1
Post NMDA receptor activation events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
protein binding	3
plasma membrane	3
intracellular membrane-bounded organelle	3
cytoplasm	3
plasma membrane region	3
actin cytoskeleton organization	2
enzyme binding	2
binding	2
endomembrane system	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
branching morphogenesis of an epithelial tube	1
ureteric bud morphogenesis	1
cell-cell recognition	1
lymphocyte activation	1
epithelial cell proliferation	1
camera-type eye development	1
anatomical structure development	1
supramolecular fiber organization	1
cellular process	1
anterograde trans-synaptic signaling	1
system development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of cell morphogenesis	1
regulation of biological quality	1
actin polymerization or depolymerization	1
protein polymerization	1
phasic smooth muscle contraction	1
actin filament polymerization	1
regulation of actin filament polymerization	1
positive regulation of protein polymerization	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
cortical cytoskeleton organization	1
spindle organization	1
cytoplasmic microtubule organization	1

Protein interactions and networks

STRING

2981 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DLG1	GRIA1	P42261	995
DLG1	GRIN2B	Q13224	970
DLG1	ADAM10	O14672	968
DLG1	AKAP5	P24588	938
DLG1	GRIN2A	Q12879	923
DLG1	LCK	P06239	909
DLG1	PTEN	P60484	904
DLG1	EPB41	P11171	892
DLG1	SCN5A	Q14524	890
DLG1	CAV3	P56539	882
DLG1	CACNG2	Q9Y698	873
DLG1	KCNA5	P22460	861
DLG1	LRFN2	Q9ULH4	860
DLG1	DLGAP1	P78335	833
DLG1	EZR	P15311	803

IntAct

1425 interactions, top by confidence:

A	B	Type	Score
DLG1	E6	psi-mi:“MI:0915”(physical association)	0.900
PIK3CA	PIK3R2	psi-mi:“MI:0914”(association)	0.900
DLG1	CYSLTR2	psi-mi:“MI:0915”(physical association)	0.840
DLG1	CYSLTR2	psi-mi:“MI:0407”(direct interaction)	0.840
DLG1	APC	psi-mi:“MI:0407”(direct interaction)	0.840
APC	DLG1	psi-mi:“MI:0407”(direct interaction)	0.840
DLG1	E6	psi-mi:“MI:0915”(physical association)	0.820
RALBP1	DLG1	psi-mi:“MI:0915”(physical association)	0.790
GRIN2B	DLG1	psi-mi:“MI:0915”(physical association)	0.790
DLG1	KCNA4	psi-mi:“MI:0915”(physical association)	0.790
DLG1	GRIN2B	psi-mi:“MI:0407”(direct interaction)	0.790
DLG1	RALBP1	psi-mi:“MI:0407”(direct interaction)	0.790
RNF146	TNKS	psi-mi:“MI:0914”(association)	0.790
DLG1	CTNND2	psi-mi:“MI:0915”(physical association)	0.720
FRMPD4	DLG1	psi-mi:“MI:0915”(physical association)	0.720
PKP4	DLG1	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (394): DLG1 (Affinity Capture-MS), DLG1 (Affinity Capture-Western), DLG1 (Affinity Capture-MS), NET1 (Affinity Capture-Western), DLG1 (Affinity Capture-MS), DLG1 (Affinity Capture-MS), DLG1 (Affinity Capture-MS), DLG1 (Two-hybrid), DLG1 (Proximity Label-MS), DLG1 (Affinity Capture-MS), DLG1 (Affinity Capture-MS), DLG1 (Affinity Capture-MS), DLG1 (Co-localization), DLG1 (Co-localization), DLG1 (Co-localization)

ESM2 similar proteins: A0A8C0TYJ0, A0A8I5ZNK2, A2AWA9, A6QQZ7, A8KBF6, O55047, O88506, O95747, P20936, P23727, P26450, P27986, P31016, P78352, Q08CW1, Q08E27, Q12959, Q15139, Q15700, Q1ECX4, Q28C55, Q5PYH5, Q5PYH6, Q5PYH7, Q5R372, Q5R495, Q5R685, Q5R6Y5, Q5RAN1, Q5RCW6, Q5SRX1, Q5T2T1, Q5U2Y3, Q5ZIL4, Q5ZMW5, Q62101, Q62108, Q62696, Q63622, Q68FK8

Diamond homologs: A0A8C0TYJ0, A0A8P0N4K0, B4F7E7, D3ZAA9, E2QY99, E2QYC9, E7FDW2, F1MAD2, G5ECY0, O14910, O15018, O55164, O75970, O84033, O88382, O88951, O88952, P15454, P31006, P31007, P31016, P46195, P57105, P68907, P70175, P78352, P93757, Q0P5F3, Q0SS73, Q0TPK6, Q12959, Q13425, Q13884, Q14160, Q15700, Q16774, Q24210, Q255A8, Q28C55, Q2KIB6

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
CDK1	unknown	DLG1	phosphorylation
CDK2	up-regulates	DLG1	phosphorylation
DLG1	“form complex”	Scribble_complex_DLG1-LLGL1_variant	binding
DLG1	“up-regulates activity”	ZAP70	phosphorylation
DLG1	“up-regulates activity”	p38	binding
CAMK2A	“down-regulates activity”	DLG1	phosphorylation
EPB41	“up-regulates activity”	DLG1	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 127 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
Assembly and cell surface presentation of NMDA receptors	6	18.8×	4e-04
RHOF GTPase cycle	5	16.0×	2e-03
RND2 GTPase cycle	5	16.0×	2e-03
Neurexins and neuroligins	5	12.2×	5e-03
CDC42 GTPase cycle	8	7.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	105
Likely benign	18
Benign	9

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1340842	GRCh37/hg19 3q29(chr3:196897651-197081796)x1	Pathogenic
562864	GRCh37/hg19 3q29(chr3:195703615-197348575)x1	Pathogenic
816511	GRCh37/hg19 3q29(chr3:195652973-197346971)x1	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000009622 (3:197133009 A>G), RS1000024814 (3:197193690 T>C), RS1000026288 (3:197050404 C>T), RS1000058538 (3:197211236 T>C), RS1000066578 (3:197154247 A>G), RS1000073642 (3:197114070 T>C), RS1000094014 (3:197240929 A>C), RS1000102289 (3:197049704 C>A), RS1000106497 (3:197049974 T>C), RS1000112947 (3:197206323 A>G), RS1000123322 (3:197220003 C>A), RS1000130689 (3:197064167 A>C,G), RS1000165415 (3:197206641 T>C), RS1000174261 (3:197165974 T>A,C), RS1000193811 (3:197085807 ACATAT>A)

Disease associations

OMIM: gene MIM:601014 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
Brugada syndrome	Limited	Unknown
cleft lip/palate	Limited	Autosomal dominant

Mondo (2): Brugada syndrome (MONDO:0015263), cleft lip/palate (MONDO:0016044)

Orphanet (1): Orofacial clefting syndrome (Orphanet:139039)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000220	Velopharyngeal insufficiency
HP:0000327	Hypoplasia of the maxilla
HP:0000403	Recurrent otitis media
HP:0000405	Conductive hearing impairment
HP:0000689	Dental malocclusion
HP:0000750	Delayed speech and language development
HP:0001611	Hypernasal speech
HP:0002033	Poor suck
HP:0004395	Malnutrition
HP:0006292	Abnormality of dental eruption
HP:0006342	Peg-shaped maxillary lateral incisors
HP:0008872	Feeding difficulties in infancy
HP:0009088	Speech articulation difficulties
HP:0010294	Palate fistula
HP:0011044	Abnormal number of permanent teeth
HP:0100334	Unilateral cleft palate
HP:0100337	Bilateral cleft palate
HP:0200136	Oral-pharyngeal dysphagia
HP:0200153	Agenesis of lateral incisor

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Valproic Acid	decreases expression	3
trichostatin A	increases expression	2
cobaltous chloride	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Tetrachlorodibenzodioxin	increases expression	2
Cadmium Chloride	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
geldanamycin	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
lead acetate	decreases expression, decreases reaction, increases abundance	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	increases expression, affects cotreatment, affects localization	1
decabromobiphenyl ether	increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
tetrabromobisphenol A	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
coumarin	decreases phosphorylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00702117	PHASE4	COMPLETED	Ajmaline Utilization in the Diagnosis and Treatment of Cardiac Arrhythmias
NCT04234971	PHASE4	RECRUITING	Cost Effectiveness in Alveolar Bone Grafting in Patients With Cleft Lip and Palate
NCT04771156	PHASE4	RECRUITING	Ketorolac in Palatoplasty
NCT00701077	PHASE3	TERMINATED	DAPERB 3,4-DiAminoPyridine and Electrophysiological Response in Brugada Syndrome
NCT00927732	PHASE3	TERMINATED	Hydroquinidine Versus Placebo in Patients With Brugada Syndrome
NCT03766217	PHASE3	COMPLETED	Bone Tissue Engineering With Dental Pulp Stem Cells for Alveolar Cleft Repair
NCT06284434	PHASE3	RECRUITING	Liposomal Bupivacaine Use in Alveolar Bone Graft Patients
NCT02933437	PHASE2	UNKNOWN	The Response To Ajmaline Provocation in Healthy Subjects
NCT07146880	PHASE2	NOT_YET_RECRUITING	Empagliflozin as a Potential Therapeutic Solution for Patients With Brugada Syndrome
NCT00930124	PHASE2	COMPLETED	Cleft Orthognathic Surgery Versus Distraction Osteogenesis - Which is Better?
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT02014961	Not specified	UNKNOWN	Worm Study: Modifier Genes in Sudden Cardiac Death
NCT02052765	Not specified	COMPLETED	AnalyST & Brugada Syndrome - Feasibility Study
NCT02302274	Not specified	COMPLETED	Diagnostic Value and Safety of Flecainide Infusion Test in Brugada Syndrome
NCT02344277	Not specified	COMPLETED	Evaluation of Subcutaneous Implantable Cardiac Defibrillator in Brugada Patients
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02641431	Not specified	COMPLETED	Epicardial Ablation in Brugada Syndrome
NCT02704416	Not specified	COMPLETED	Ablation in Brugada Syndrome for the Prevention of VF
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03435393	Not specified	UNKNOWN	Ripple Mapping for Epicardial Mapping of Brugada Syndrome
NCT03485508	Not specified	UNKNOWN	The Brugada Syndrome: a Follow-up Study
NCT03491475	Not specified	UNKNOWN	Echocardiography During Ajmaline Test
NCT03524079	Not specified	COMPLETED	Right Ventricle Morphology and Hemodynamics in BrS
NCT03764592	Not specified	COMPLETED	VF Mapping in Brugada and Early Repolarization Syndromes
NCT03775954	Not specified	RECRUITING	Fetal Electrophysiologic Abnormalities in High-Risk Pregnancies Associated With Fetal Demise
NCT03992677	Not specified	COMPLETED	Feasibility of Improving Risk Stratification in Brugada Syndrome
NCT04124237	Not specified	COMPLETED	Long Term Monitoring for Risk of Sudden Death
NCT04232787	Not specified	UNKNOWN	Southeast Asian Brugada Syndrome Cohort
NCT04257994	Not specified	RECRUITING	Distribution of Cell-cell Junction Proteins in Arrhythmic Disorders
NCT04420078	Not specified	COMPLETED	Brugada Ablation of VF Substrate Ongoing MultiCenter Registry
NCT04580992	Not specified	UNKNOWN	Defining the Electrocardiographic Effect of Propofol on the Ajmaline Provocation Drug Challenge: A Prospective Trial
NCT04650009	Not specified	COMPLETED	Physical Activity in Children With Inherited Cardiac Diseases
NCT04712136	Not specified	COMPLETED	Healthy-related Quality of Life and Physical Activity of Children With Cardiac Malformations
NCT04808193	Not specified	UNKNOWN	European Perioperative Brugada Survey
NCT05048602	Not specified	UNKNOWN	Drug-induced Brugada Syndrome Research Database
NCT05274646	Not specified	COMPLETED	Impact on Risk Stratification of Overlap Syndrome Phenotype in Patients With E1784K Mutation in SCN5A
NCT05283759	Not specified	RECRUITING	UZ Brussel HRMC Registry of Brugada Syndrome
NCT05521451	Not specified	RECRUITING	Clinical Cohort Study - TRUST
NCT05643209	Not specified	RECRUITING	Brugada Syndrome Substrate Characterization and Ablation
NCT05685134	Not specified	COMPLETED	Epicardial Radiofrequency Catheter Ablation in Patients With Brugada Syndrome