DAG1

Summary

DAG1 (dystroglycan 1, HGNC:2666) is a protein-coding gene on chromosome 3p21.31, encoding Dystroglycan 1 (Q14118). The dystroglycan complex is involved in a number of signaling events and processes including laminin deposition and extracellular matrix assembly, acetylcholine receptor clustering, sarcolemmal stability, cell survival, peripheral nerve myelination, nodal structure, cell migrati….

This gene encodes dystroglycan, a central component of dystrophin-glycoprotein complex that links the extracellular matrix and the cytoskeleton in the skeletal muscle. The encoded preproprotein undergoes O- and N-glycosylation, and proteolytic processing to generate alpha and beta subunits. Certain mutations in this gene are known to cause distinct forms of muscular dystrophy. Alternative splicing results in multiple transcript variants, all encoding the same protein.

Source: NCBI Gene 1605 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 23
• Clinical variants (ClinVar): 770 total — 12 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 94
• Druggable target: yes
• MANE Select transcript: NM_004393

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2666
Approved symbol	DAG1
Name	dystroglycan 1
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	A3a, 156DAG, AGRNR, DAG
Ensembl gene	ENSG00000173402
Ensembl biotype	protein_coding
OMIM	128239
Entrez	1605

Gene structure

Transcript identifiers

Ensembl transcripts: 73 — 68 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000308775, ENST00000418588, ENST00000421560, ENST00000428779, ENST00000430636, ENST00000431960, ENST00000435508, ENST00000452060, ENST00000452317, ENST00000461492, ENST00000461987, ENST00000466701, ENST00000469139, ENST00000475424, ENST00000479935, ENST00000496474, ENST00000673708, ENST00000697270, ENST00000697271, ENST00000882459, ENST00000882460, ENST00000882461, ENST00000882462, ENST00000882463, ENST00000882464, ENST00000882465, ENST00000882466, ENST00000882467, ENST00000882468, ENST00000882469, ENST00000882470, ENST00000882471, ENST00000882472, ENST00000882473, ENST00000882474, ENST00000882475, ENST00000882476, ENST00000882477, ENST00000882478, ENST00000882479, ENST00000882480, ENST00000882481, ENST00000882482, ENST00000882483, ENST00000882484, ENST00000882485, ENST00000882486, ENST00000882487, ENST00000936846, ENST00000936847, ENST00000936848, ENST00000936849, ENST00000936850, ENST00000936851, ENST00000936852, ENST00000936853, ENST00000936854, ENST00000936855, ENST00000936856, ENST00000936857, ENST00000936858, ENST00000936859, ENST00000936860, ENST00000936861, ENST00000936862, ENST00000936863, ENST00000936864, ENST00000936865, ENST00000966346, ENST00000966347, ENST00000966348, ENST00000966349, ENST00000966350

RefSeq mRNA: 13 — MANE Select: NM_004393 NM_001165928, NM_001177634, NM_001177635, NM_001177636, NM_001177637, NM_001177638, NM_001177639, NM_001177640, NM_001177641, NM_001177642, NM_001177643, NM_001177644, NM_004393

CCDS: CCDS2799

Canonical transcript exons

ENST00000308775 — 3 exons

Exon	Start	End
ENSE00001929502	49510419	49510819
ENSE00003897706	49470267	49470433
ENSE00003970099	49530797	49535615

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.7763 / max 404.4633, expressed in 1810 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36632	41.9532	1809
36629	4.2518	1344
36630	1.2062	714
36634	0.8262	562
36633	0.2997	152
36631	0.1699	47
36628	0.0601	17
202752	0.0091	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	99.20	gold quality
trigeminal ganglion	UBERON:0001675	98.31	gold quality
dorsal root ganglion	UBERON:0000044	98.05	gold quality
renal glomerulus	UBERON:0000074	97.75	gold quality
metanephric glomerulus	UBERON:0004736	97.64	gold quality
pancreatic ductal cell	CL:0002079	96.52	gold quality
endometrium epithelium	UBERON:0004811	96.38	gold quality
parotid gland	UBERON:0001831	96.20	gold quality
placenta	UBERON:0001987	96.20	gold quality
nipple	UBERON:0002030	96.14	gold quality
saphenous vein	UBERON:0007318	96.13	gold quality
gluteal muscle	UBERON:0002000	96.10	gold quality
quadriceps femoris	UBERON:0001377	96.05	gold quality
tibia	UBERON:0000979	95.99	gold quality
vastus lateralis	UBERON:0001379	95.90	gold quality
tibialis anterior	UBERON:0001385	95.87	gold quality
secondary oocyte	CL:0000655	95.85	gold quality
triceps brachii	UBERON:0001509	95.83	gold quality
upper arm skin	UBERON:0004263	95.77	gold quality
left ventricle myocardium	UBERON:0006566	95.73	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.60	gold quality
gastrocnemius	UBERON:0001388	95.57	gold quality
skeletal muscle tissue	UBERON:0001134	95.48	gold quality
body of tongue	UBERON:0011876	95.45	gold quality
muscle tissue	UBERON:0002385	95.42	gold quality
deltoid	UBERON:0001476	95.30	gold quality
muscle organ	UBERON:0001630	95.29	gold quality
skeletal muscle organ	UBERON:0014892	95.29	gold quality
vena cava	UBERON:0004087	95.19	gold quality
muscle of leg	UBERON:0001383	95.15	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	16.39
E-ANND-3	yes	12.61
E-MTAB-6142	no	175.62

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

miRNA regulators (miRDB)

202 targeting DAG1, 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-1252-5P	100.00	69.80	2774
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-3163	100.00	77.23	8605
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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-568	99.98	69.86	2084
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504

Literature-anchored findings (GeneRIF, showing 40)

• Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. (PMID:12140558)
• Glomeruli possess large amounts of a specifically composed complex; this complex may undergo changes in human glomerular disease; and flattening of foot processes is directly associated with dissociation of laminin-dystroglycan complexes. (PMID:12386278)
• hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumours and interact with metastasis gene C4.4a and dystroglycan. (PMID:12592373)
• Expression is frequently reduced in human breast and colon cancers and is associated with tumor progression. (PMID:12598319)
• in human coxsackievirus B myocarditis a focal disruption of the DAG can principally occur and may contribute to the pathogenesis of human enterovirus-induced dilated cardiomyopathy (PMID:12920582)
• mutation of certain residues prevents both ezrin binding and the induction of actin-rich surface protrusions (PMID:15175275)
• Cells that are defective in components of the O-mannosylation pathway showed strikingly reduced lymphocytic choriomeningitis virus infectbility. (PMID:16254364)
• alpha-DG glycosylation may differ between neurons and glial cells in congenital musculaar dystrophy brains. (PMID:16466646)
• DG may be involved in the progression of primary brain tumors (PMID:16575202)
• Fukutin seems to bind to both the hypoglycosylated and fully glycosylated form of alpha-dystroglycan, and seems bind to the core area rather than the sugar chain of alpha-dystroglycan (PMID:17005282)
• muscle-specific receptor tyrosine kinase activation and binding to dystroglycan are regulated by alternative mRNA splicing of agrin (PMID:17012237)
• Data suggest that disturbances in the function of the dystroglycan complex might contribute to the definition of the malignant behavior of prostate cancer cells and suggest that androgens might regulate DG expression in these cells. (PMID:17516554)
• alpha dystroglycan glycosylation & laminin binding to alpha dystroglycan are altered in certain pediatric solid tumors and suggest that aberrant dystroglycan glycosylation may contribute to tumor cell biology in patients with RMS, medulloblastoma, & NBL. (PMID:17640712)
• Loss of alphaDG expression, which correspond to loss of a functional DG complex, is a frequent event in human renal tumorigenesis and is an independent predictor of early recurrence and death for patients with clear cell RCC. (PMID:18087214)
• Initiation of mammalian O-mannosylation in vivo is independent of a consensus sequence and controlled by peptide regions within and upstream of the alpha-dystroglycan mucin domain. (PMID:18456664)
• These data indicate that it is not always possible to correlate clinical course and alpha-dystroglycan labeling and suggest that there might be differences in alpha-dystroglycan processing in muscular dystrophies. (PMID:18691338)
• transmembrane subunits of both MUC1 and DG transit the secretory pathway prior to nuclear targeting and that their monomeric precursors maintain the capacity for nuclear trafficking (PMID:18764929)
• Biochemical analysis revealed altered glycosylation and decreased laminin-binding activity of alpha-dystroglycan in congenital muscular dystrophy. we focus on the molecular pathomechanism and diverging clinical phenotypes of alpha-dystroglycanopathy. (PMID:18939472)
• Dystroglycan was strongly expressed at the intercellular junctions and basement membranes of all normal human epithelia. (PMID:18983465)
• LARGE repression is responsible for the defects in dystroglycan-mediated cell adhesion that are observed in epithelium-derived cancer cells and point to a defect of dystroglycan glycosylation as a factor in cancer progression (PMID:19244252)
• These results identify a previously undescribed role of carbohydrate-dependent cell-basement membrane interaction in tumor suppression and its control by beta3GnT1 and LARGE. (PMID:19587235)
• analysis of the main cleavage site involved in enzymatic processing of beta-dystroglycan recombinant ectodomain by MMP-9 (PMID:19946898)
• study identified phosphorylated O-mannosyl glycan on mucin-like domain of alpha-DG, which was required for laminin binding; patients with muscular dystrophy have defects in a postphosphoryl modification of this phosphorylated O-linked mannose (PMID:20044576)
• Reduced expression and altered localization of dystroglycan is common in pancreatic cancer, potentially contributing to the aggressive behavior of this disease. (PMID:20338590)
• Loss of alpha-dystroglycan expression is a frequent event in human oral squamous cell carcinoma (PMID:20350218)
• Twenty-five glycopeptides were characterized from human alpha-dystroglycan, which provide insight to the complex in vivo O-glycosylation of alpha-dystroglycan. (PMID:20507882)
• Beta-dystroglycan follows a conventional Importin alpha/beta-dependent nuclear import pathway (PMID:20512930)
• Biological role of dystroglycan in Schwann cell function, especially myelination, and its implications in diseases is reviewed. (PMID:20625412)
• Data show that loss of nuclear p27(kip1) is a frequent event in human RCCs and is a powerful predictor of poor outcome which, in combination with low DG expression, could help to identify high-risk patients with clear cell RCC. (PMID:20626751)
• Beta-Dystroglycan interaction with caveolin-1 in smooth muscle is required for receptor-mediated Ca2+ release. (PMID:20736308)
• LARGE has a role in inducing alpha-dystroglycan hyperglycosylation in skeletal and cardiac muscle (PMID:21203384)
• Ameloblastoma cells proliferate and are differentiated by capturing perlecan differentially with alpha-dystroglycan and integrin beta1, respectively (PMID:21255062)
• a mechanism by which Large competes with galactosyltransferase to target GlcNAc terminals to induce the functional glycans on alpha-DG (PMID:21347376)
• These observations suggest that secreted alpha-DG-N may be transported via CSF and have yet unidentified effects on the nervous system. (PMID:21741360)
• Studies indicate that the cylindromatosis/turban tumor syndrome gene (CYLD) ranked highest, followed by acylaminoacyl-peptidase (APEH), dystroglycan (DAG1), macrophage-stimulating protein (MST1) and ubiquitin-specific peptidase 4 (USP4). (PMID:21931648)
• the ligand-binding activity of alpha-dystroglycan is conferred primarily by LARGE modification at Thr-317 and -319, within the highly conserved first 18 amino acids of the mucin-like domain (PMID:21987822)
• Data suggest that throughout pregnancy, changes occur in expression and distribution of DAG1 and dystroglycan subunits in placental tissues undergoing placentation. (PMID:22138543)
• Dynamics of expression patterns of dystroglycan in human glioblastoma (PMID:22307776)
• The virus-induced perturbation of alpha6beta1 integrin signalling critically depended on high-affinity Lassa virus binding to dystroglycan and dystroglycan’s cytoplasmic domain. (PMID:22405130)
• novel role for HNK-1ST as a tumor suppressor controlling the functional glycans on alpha-DG and the importance of sulfate transfer in the glycosylation of alpha-DG. (PMID:22801424)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	dag1	ENSDARG00000016153
mus_musculus	Dag1	ENSMUSG00000039952
rattus_norvegicus	Dag1	ENSRNOG00000019400
drosophila_melanogaster	Dg	FBGN0034072
caenorhabditis_elegans		WBGENE00000961
caenorhabditis_elegans		WBGENE00018943

Protein

Protein identifiers

Dystroglycan 1 — Q14118 (reviewed: Q14118)

Alternative names: Dystroglycan, Dystrophin-associated glycoprotein 1

All UniProt accessions (10): A0A1D5RMP6, A0A669KB80, C9J196, C9J6Z6, C9JEH2, C9JEN1, C9JQL4, C9JY76, C9JYS1, Q14118

UniProt curated annotations — full annotation on UniProt →

Function. The dystroglycan complex is involved in a number of signaling events and processes including laminin deposition and extracellular matrix assembly, acetylcholine receptor clustering, sarcolemmal stability, cell survival, peripheral nerve myelination, nodal structure, cell migration, epithelial polarization, and epithelium branching morphogenesis. Required for the formation of photoreceptor ribbon synapses, and long-term maintenance of inhibitory synapses in cerebellar Purkinje cells. Also involved in the positive regulation of cartilage formation through agrin (AGRN) binding and up-regulation of SOX9, a transcription factor that plays a key role in chondrocytes differentiation. Extracellular peripheral glycoprotein that acts as a receptor for extracellular matrix proteins containing laminin-G domains. As a receptor for laminin is involved in extracellular matrix assembly, and activation of the PI3K/AKT pathway regulating cell apoptotic signals in muscle. Binding of laminin LAMA1 to alpha-dystroglycan also initiates a signaling cascade in which Src kinases, c-Src or c-Fyn, phosphorylate syntrophin modifying its interaction with the adapter protein GRB2; this triggers recruitment of guanyl-nucleotide exchange factor SOS1 and activation of RAC1, finally resulting in c-Jun phosphorylation by MAPK8/JNK1. As a receptor for laminin LAMA1 is also involved in epithelium branching morphogenesis in salivary glang and lung. Receptor for laminin-2 (LAMA2) and agrin in peripheral nerve Schwann cells. Also acts as a receptor for laminin LAMA5. In muscle cells, it is a receptor for laminin-1 (also known as laminin-111 or EHS laminin) and is involved in the stimulation of agrin-induced acetylcholine receptor (AChR) clustering, and formation of the synaptic basement membrane. It is required for acetylcholinesterase (AChE) localization at the neuromuscular junctions (NMJ) through its binding with perlecan (HSPG2) and is, therefore, involved in the down-regulation of colinergic synaptic transmission. In the retina, it is required for the formation of photoreceptor ribbon synapses through its interaction with pikachurin (EGFLAM). Involved in the positive regulation of cartilage formation through agrin (AGRN) binding and up-regulation of SOX9, a transcription factor that plays a key role in chondrocytes differentiation. Transmembrane protein that plays important roles in connecting the extracellular matrix to the cytoskeleton. Acts as a cell adhesion receptor in both muscle and non-muscle tissues. Receptor for both DMD and UTRN and, through these interactions, scaffolds axin to the cytoskeleton. Also functions in cell adhesion-mediated signaling and implicated in cell polarity. (Microbial infection) Acts as a receptor for lassa virus and lymphocytic choriomeningitis virus glycoprotein and class C new-world arenaviruses. Acts as a Schwann cell receptor for Mycobacterium leprae, the causative organism of leprosy, but only in the presence of the G-domain of LAMA2.

Subunit / interactions. Monomer. Heterodimer of alpha- and beta-dystroglycan subunits which are the central components of the dystrophin-glycoprotein complex. This complex then can form a dystrophin-associated glycoprotein complex (DGC) which is composed of three subcomplexes: a cytoplasmic complex comprised of DMD (or UTRN), DTNA and a number of syntrophins, such as SNTB1, SNTB2, SNTG1 and SNTG2, the transmembrane dystroglycan complex, and the sarcoglycan-sarcospan complex. Interacts (via the N-terminal of alpha-dystroglycan) with LARGE1; the interaction enhances laminin binding. Interacts with SGCD. Interacts with AGR2 and AGR3. Interacts (beta-dystroglycan) with DMD; the interaction is inhibited by phosphorylation on the PPXY motif. Interacts (beta-dystroglycan, via its PPXY motif) with UTRN (via its WWW and ZZ domains); the interaction is inhibited by phosphorylation on the PPXY motif. Interacts (beta-dystroglycan, via its phosphorylated PPXY motif) with the SH2 domain-containing proteins, FYN, CSK, NCK and SHC. Interacts (beta-dystroglycan) with CAV3 (via a central WW-like domain); the interaction disrupts the binding of DMD. Beta-dystroglycan directly interacts with ANK3, but not with ANK2; this interaction does not interfere with DMD-binding and is required for retention at costameres. Identified in a dystroglycan complex that contains at least PRX, DRP2, UTRN, DMD and DAG1. Interacts with POMGNT1. Beta-dystroglycan interacts with CD93. Alpha-dystroglycan interacts with HSPG2; the interaction is required for acetylcholinesterase (AChE) localization at the neuromuscular junctions (NMJ). Alpha-dystroglycan interacts with AGRN; the interaction is required for up-regulation of SOX9 and cartilage formation. Alpha-dystroglycan interacts with pikachurin (EGFLAM); the interaction is required for photoreceptor ribbon synapse formation. (Microbial infection) Interacts with lassa virus and lymphocytic choriomeningitis virus glycoprotein. (Microbial infection) Interacts with surface molecules of mycobacterium leprae.

Subcellular location. Secreted. Extracellular space. Extracellular matrix. Basement membrane. Synapse Cell membrane. Cytoplasm. Cytoskeleton. Nucleus. Nucleoplasm. Cell membrane. Sarcolemma. Synapse. Postsynaptic cell membrane.

Tissue specificity. Expressed in a variety of fetal and adult tissues. In epidermal tissue, located to the basement membrane. Also expressed in keratinocytes and fibroblasts.

Post-translational modifications. O-glycosylated. POMGNT1 catalyzes the initial addition of N-acetylglucosamine, giving rise to the GlcNAc(beta1-2)Man(alpha1-)O-Ser/Thr moiety and thus providing the necessary basis for the addition of further carbohydrate moieties. Heavily O-glycosylated comprising of up to two thirds of its mass and the carbohydrate composition differs depending on tissue type. Mucin-type O-glycosylation is important for ligand binding activity. O-mannosylation is found in high abundance in both brain and muscle where the most abundant glycan is Sia-alpha-2-3-Gal-beta-1-4-Glc-NAc-beta-1-2-Man. In muscle, glycosylation on Thr-317, Thr-319 and Thr-379 by a phosphorylated O-mannosyl glycan with the structure 2-(N-acetylamido)-2-deoxygalactosyl-beta-1,3-2-(N-acetylamido)-2-deoxyglucosyl-beta-1,4-6-phosphomannose is mediated by like-acetylglucosaminyltransferase (LARGE1) protein and is required for laminin binding. Glycosylation by LARGE1 is also required for perlecan binding. The O-glycosyl hexose on Thr-367, Thr-369, Thr-372, Thr-381 and Thr-388 is probably mannose. O-glycosylated in the N-terminal region with a core 1 or possibly core 8 glycan. The brain form displays a unique glycosylation pattern which is absent in other tissues; this form shows enhanced binding to laminin LAMA5 compared to the skeletal muscle form. (Microbial infection) O-mannosylation is required for binding lymphocytic choriomeningitis virus, Old World Lassa fever virus, and clade C New World arenaviruses. N-glycosylated. Autolytic cleavage produces the alpha and beta subunits. In cutaneous cells, as well as in certain pathological conditions, shedding of beta-dystroglycan can occur releasing a peptide of about 30 kDa. SRC-mediated phosphorylation of the PPXY motif of the beta subunit recruits SH2 domain-containing proteins, but inhibits binding to WWW domain-containing proteins, DMD and UTRN. This phosphorylation also inhibits nuclear entry.

Disease relevance. Muscular dystrophy-dystroglycanopathy limb-girdle C9 (MDDGC9) [MIM:613818] An autosomal recessive muscular dystrophy showing onset in early childhood, and associated with intellectual disability without structural brain anomalies. The disease is caused by variants affecting the gene represented in this entry. MDDGC7 is caused by DAG1 mutations that interfere with normal post-translational processing, resulting in defective DAG1 glycosylation and impaired interactions with extracellular-matrix components. Other muscular dystrophy-dystroglycanopathies are caused by defects in enzymes involved in protein O-glycosylation. Muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A9 (MDDGA9) [MIM:616538] An autosomal recessive disorder characterized by congenital muscular dystrophy associated with cobblestone lissencephaly and other brain anomalies, eye malformations, profound intellectual disability, and death usually in the first years of life. Included diseases are the more severe Walker-Warburg syndrome and the slightly less severe muscle-eye-brain disease. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (13): NP_001159400, NP_001171105, NP_001171106, NP_001171107, NP_001171108, NP_001171109, NP_001171110, NP_001171111, NP_001171112, NP_001171113, NP_001171114, NP_001171115, NP_004384* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006644	Cadg	Domain
IPR008465	DAG1_C	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015919	Cadherin-like_sf	Homologous_superfamily
IPR027468	Alpha-dystroglycan_domain_2	Homologous_superfamily
IPR030398	SEA_DG_dom	Domain
IPR041631	Alpha_DG1_N2	Domain

Pfam: PF05345, PF05454, PF18424

UniProt features (98 total): mutagenesis site 20, strand 15, glycosylation site 14, region of interest 10, helix 8, compositionally biased region 5, sequence variant 5, sequence conflict 4, chain 2, short sequence motif 2, site 2, modified residue 2, topological domain 2, disulfide bond 2, turn 2, signal peptide 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
5GGP	X-RAY DIFFRACTION	1.6
5LLK	X-RAY DIFFRACTION	1.8
1EG4	X-RAY DIFFRACTION	2
7E9K	X-RAY DIFFRACTION	2.05
7E9L	X-RAY DIFFRACTION	2.1
6JJY	X-RAY DIFFRACTION	2.3
8UF4	X-RAY DIFFRACTION	2.43
2MK7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14118-F1	68.44	0.32

Functional residue map

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

Catalytic / active sites (2): 653–654 (cleavage; by autolysis); 715–716 (cleavage; by mmp9)

Post-translational modifications (2): 790, 892

Disulfide bonds (2): 182–264, 669–713

Glycosylation sites (14): 63, 141, 317, 319, 367, 369, 372, 379, 381, 388, 455, 641, 649, 661

Mutagenesis-validated functional residues (20):

Position	Phenotype
311–370	abolishes large1-dependent glycosylation, chst10-dependent sulfation and consequent binding to laminin; when associated
317–319	impaired laminin-binding.
328–329	does not affect laminin-binding.
368–461	retains the capacity to bind laminin.
379	abolishes large1-dependent glycosylation, chst10-dependent sulfation and consequent binding to laminin; when associated
654	abolishes autoproteolysis and enhances laminin-binding.
663	reduced n-linked glycosylation. no change in nuclear translocation.
776–782	moderate reduction in nuclear accumulation.
777–782	about 50% reduction in nuclear accumulation.
777–782	drastic reduction in nuclear accumulation.
777–780	abolishes nuclear translocation.
779	significant reduction in nuclear accumulation.
780	significant reduction in nuclear accumulation.
793–794	abolishes nuclear translocation.
823	no change in nuclear location.
828–829	no change in nuclear location.
831	no change in nuclear location.
892	abolishes phosphorylation. no change in plasma membrane location.
892	redistributes to a vesicular internal membrane compartment.
892	abolishes phosphorylation. increase in nuclear location.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-3000171	Non-integrin membrane-ECM interactions
R-HSA-3000178	ECM proteoglycans
R-HSA-5083628	Defective POMGNT1 causes MDDGA3, MDDGB3 and MDDGC3
R-HSA-5083629	Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2
R-HSA-5083633	Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1
R-HSA-8932504	DAG1 core M2 glycosylations
R-HSA-8932505	DAG1 core M3 glycosylations
R-HSA-8932506	DAG1 core M1 glycosylations
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-9619665	EGR2 and SOX10-mediated initiation of Schwann cell myelination
R-HSA-9913351	Formation of the dystrophin-glycoprotein complex (DGC)
R-HSA-9939291	Matriglycan biosynthesis on DAG1

MSigDB gene sets: 738 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, TGGTGCT_MIR29A_MIR29B_MIR29C, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_SKELETAL_MUSCLE_TISSUE_REGENERATION, GOBP_GLAND_MORPHOGENESIS, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_MICROTUBULE_ANCHORING, GOBP_SYNAPSE_ASSEMBLY, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_SALIVARY_GLAND_DEVELOPMENT

GO Biological Process (41): positive regulation of cell-matrix adhesion (GO:0001954), morphogenesis of an epithelium (GO:0002009), morphogenesis of an epithelial sheet (GO:0002011), heart morphogenesis (GO:0003007), membrane protein ectodomain proteolysis (GO:0006509), axon guidance (GO:0007411), response to muscle activity (GO:0014850), response to denervation involved in regulation of muscle adaptation (GO:0014894), protein transport (GO:0015031), muscle attachment (GO:0016203), calcium-dependent cell-matrix adhesion (GO:0016340), nerve development (GO:0021675), nerve maturation (GO:0021682), myelination in peripheral nervous system (GO:0022011), extracellular matrix organization (GO:0030198), negative regulation of cell migration (GO:0030336), axon regeneration (GO:0031103), positive regulation of myelination (GO:0031643), microtubule anchoring (GO:0034453), positive regulation of Rac protein signal transduction (GO:0035022), skeletal muscle tissue regeneration (GO:0043403), negative regulation of MAPK cascade (GO:0043409), response to peptide hormone (GO:0043434), regulation of synaptic plasticity (GO:0048167), positive regulation of oligodendrocyte differentiation (GO:0048714), regulation of synapse organization (GO:0050807), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), angiogenesis involved in wound healing (GO:0060055), epithelial tube branching involved in lung morphogenesis (GO:0060441), branching involved in salivary gland morphogenesis (GO:0060445), cellular response to mechanical stimulus (GO:0071260), cellular response to cholesterol (GO:0071397), commissural neuron axon guidance (GO:0071679), basement membrane organization (GO:0071711), regulation of neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0098696), retrograde trans-synaptic signaling by trans-synaptic protein complex (GO:0098942), inhibitory synapse assembly (GO:1904862), heart development (GO:0007507), Schwann cell differentiation (GO:0014037), Schwann cell development (GO:0014044)

GO Molecular Function (15): virus receptor activity (GO:0001618), dystroglycan binding (GO:0002162), actin binding (GO:0003779), serine-type endopeptidase activity (GO:0004252), laminin receptor activity (GO:0005055), calcium ion binding (GO:0005509), structural constituent of muscle (GO:0008307), tubulin binding (GO:0015631), vinculin binding (GO:0017166), SH2 domain binding (GO:0042169), laminin binding (GO:0043236), laminin-1 binding (GO:0043237), protein-containing complex binding (GO:0044877), alpha-actinin binding (GO:0051393), protein binding (GO:0005515)

GO Cellular Component (40): Golgi membrane (GO:0000139), extracellular region (GO:0005576), basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum membrane (GO:0005789), Golgi lumen (GO:0005796), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), adherens junction (GO:0005912), focal adhesion (GO:0005925), external side of plasma membrane (GO:0009897), dystrophin-associated glycoprotein complex (GO:0016010), dystroglycan complex (GO:0016011), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), lamellipodium (GO:0030027), filopodium (GO:0030175), extracellular matrix (GO:0031012), node of Ranvier (GO:0033268), nuclear periphery (GO:0034399), sarcolemma (GO:0042383), costamere (GO:0043034), plasma membrane raft (GO:0044853), postsynaptic membrane (GO:0045211), extracellular exosome (GO:0070062), contractile ring (GO:0070938), photoreceptor ribbon synapse (GO:0098684), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), postsynaptic cytosol (GO:0099524), nucleus (GO:0005634), cell-cell junction (GO:0005911), cell surface (GO:0009986), membrane raft (GO:0045121), synapse (GO:0045202), postsynapse (GO:0098794)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
DAG1 glycosylations	4
Diseases associated with O-glycosylation of proteins	3
Extracellular matrix organization	2
Signaling by ROBO receptors	1
Nervous system development	1
Non-integrin membrane-ECM interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoskeletal protein binding	3
cell-matrix adhesion	2
myelination	2
protein binding	2
laminin binding	2
binding	2
Golgi apparatus	2
intracellular organelle lumen	2
plasma membrane protein complex	2
regulation of cell-matrix adhesion	1
positive regulation of cell-substrate adhesion	1
tissue morphogenesis	1
epithelium development	1
morphogenesis of an epithelium	1
heart development	1
animal organ morphogenesis	1
membrane protein proteolysis	1
axonogenesis	1
neuron projection guidance	1
response to activity	1
response to muscle inactivity	1
regulation of muscle adaptation	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
multicellular organismal process	1
skeletal muscle organ development	1
nervous system development	1
anatomical structure development	1
nerve development	1
anatomical structure maturation	1
Schwann cell development	1
peripheral nervous system axon ensheathment	1
extracellular structure organization	1
external encapsulating structure organization	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
neuron projection regeneration	1

Protein interactions and networks

STRING

1970 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DAG1	DMD	P11532	999
DAG1	AGRN	O00468	999
DAG1	SSPN	Q14714	997
DAG1	SGCA	Q16586	997
DAG1	NRXN2	Q9P2S2	997
DAG1	UTRN	P46939	997
DAG1	HSPG2	P98160	996
DAG1	NRXN1	Q9ULB1	996
DAG1	LAMA2	P24043	996
DAG1	EGFLAM	Q63HQ2	994
DAG1	SGCD	Q92629	993
DAG1	SGCG	Q13326	990
DAG1	FKRP	Q9H9S5	978
DAG1	POMT1	Q9Y6A1	978
DAG1	FKTN	O75072	977

IntAct

128 interactions, top by confidence:

A	B	Type	Score
TSPAN15	ADAM10	psi-mi:“MI:0914”(association)	0.840
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TNFSF8	TOR1B	psi-mi:“MI:0914”(association)	0.640
SLC16A3	CASK	psi-mi:“MI:0914”(association)	0.590
DAG1	DAG1	psi-mi:“MI:0407”(direct interaction)	0.560
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
TCTN2	TPST2	psi-mi:“MI:0914”(association)	0.530
PCDHAC2	TMEM223	psi-mi:“MI:0914”(association)	0.530
HLA-DPA1	TYW5	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
BTNL3	FAM171A2	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
FKBP9	CASC3	psi-mi:“MI:0914”(association)	0.530
TNF	B4GALT5	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
TNFSF8	LGALS8	psi-mi:“MI:0914”(association)	0.530
LGALS1	LAMA5	psi-mi:“MI:0914”(association)	0.530
RYK	PCDH7	psi-mi:“MI:0914”(association)	0.530
GPRC5B	STXBP3	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
DMD	DAG1	psi-mi:“MI:0407”(direct interaction)	0.440
Grb2	DAG1	psi-mi:“MI:0407”(direct interaction)	0.440
SRC	DAG1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (203): DAG1 (Affinity Capture-MS), DAG1 (Affinity Capture-MS), DAG1 (Affinity Capture-MS), DAG1 (Affinity Capture-MS), DAG1 (Affinity Capture-MS), DAG1 (Affinity Capture-MS), DAG1 (Affinity Capture-MS), DAG1 (Affinity Capture-MS), DAG1 (Co-fractionation), DAG1 (Co-fractionation), DAG1 (Co-fractionation), DAG1 (Co-fractionation), DAG1 (Synthetic Lethality), DAG1 (Reconstituted Complex), DAG1 (Proximity Label-MS)

ESM2 similar proteins: A2RUV9, F8W3R9, O18738, O43278, O54858, O88393, O97827, P00734, P00735, P0C5J5, P12259, P18292, P26342, P35054, P51511, Q08629, Q08E66, Q09101, Q14118, Q24567, Q24568, Q28685, Q29243, Q5R537, Q5RD69, Q62165, Q62288, Q640N1, Q66K79, Q701R2, Q7TQN3, Q80TS3, Q8BKV0, Q8IUX7, Q8N436, Q8R4V4, Q8TEU8, Q91ZV2, Q91ZV3, Q92563

Diamond homologs: O18738, Q14118, Q28685, Q29243, Q62165, Q9TSZ6

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
SRC	down-regulates	DAG1	phosphorylation
DAG1	“form complex”	DGC	binding
POMT	“up-regulates activity”	DAG1	glycosylation
NRXN1	“up-regulates activity”	DAG1	binding
NRXN2	“up-regulates activity”	DAG1	binding
NRXN3	“up-regulates activity”	DAG1	binding
“Fukutin-FKRP-TMEM5 multienzyme complex”	“up-regulates activity”	DAG1	glycosylation
ANK3	“up-regulates quantity”	DAG1	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 140 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
Constitutive Signaling by EGFRvIII	6	46.5×	2e-07
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	8	45.1×	3e-09
Signaling by ERBB2 ECD mutants	6	43.8×	3e-07
GRB2 events in EGFR signaling	5	41.4×	3e-06
Signaling by FLT3 ITD and TKD mutants	5	41.4×	3e-06
Tie2 Signaling	6	39.2×	4e-07
SHC1 events in EGFR signaling	5	38.8×	5e-06
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	6	37.2×	5e-07

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of interleukin-1 beta production	5	11.1×	1e-02
positive regulation of T cell proliferation	5	11.1×	1e-02
T cell activation	5	11.1×	1e-02
Ras protein signal transduction	6	10.5×	4e-03
positive regulation of tumor necrosis factor production	7	9.2×	3e-03
T cell receptor signaling pathway	6	7.8×	1e-02
positive regulation of ERK1 and ERK2 cascade	10	7.3×	7e-04
protein localization to plasma membrane	7	6.5×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	12
Uncertain significance	453
Likely benign	196
Benign	24

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1073860	NM_004393.6(DAG1):c.41C>A (p.Ser14Ter)	Pathogenic
208543	NM_004393.6(DAG1):c.743del (p.Ala248fs)	Pathogenic
3246914	NC_000003.11:g.(?49568210)(49570632_?)del	Pathogenic
3765747	NM_004393.6(DAG1):c.915del (p.Leu306fs)	Pathogenic
418678	NM_004393.6(DAG1):c.1771_1796del (p.Phe591fs)	Pathogenic
4785636	NM_004393.6(DAG1):c.1056_1057del (p.Glu352fs)	Pathogenic
4786300	NM_004393.6(DAG1):c.616del (p.Gln206fs)	Pathogenic
539125	NM_004393.6(DAG1):c.440del (p.Gln147fs)	Pathogenic
654870	NM_004393.6(DAG1):c.235C>T (p.Arg79Ter)	Pathogenic
833037	NC_000003.12:g.(?49121216)(49533209_?)del	Pathogenic
842859	NM_004393.6(DAG1):c.285+1G>A	Pathogenic
958922	NM_004393.6(DAG1):c.330G>A (p.Trp110Ter)	Pathogenic
1691444	NM_004393.6(DAG1):c.839del (p.Pro280fs)	Likely pathogenic
1709072	NM_004393.6(DAG1):c.721_722del (p.Phe241fs)	Likely pathogenic
290435	NM_004393.6(DAG1):c.1257del (p.Thr421fs)	Likely pathogenic
3233447	NM_004393.6(DAG1):c.112del (p.Ala38fs)	Likely pathogenic
3338231	NM_004393.6(DAG1):c.255_258delinsCC (p.Leu86fs)	Likely pathogenic
429641	NM_004393.6(DAG1):c.310_311del (p.Leu104fs)	Likely pathogenic
432120	NM_004393.6(DAG1):c.891G>A (p.Trp297Ter)	Likely pathogenic
471776	NM_004393.6(DAG1):c.454_467del (p.Phe152fs)	Likely pathogenic
4821383	NM_004393.6(DAG1):c.1282C>T (p.Arg428Ter)	Likely pathogenic
497506	NM_004393.6(DAG1):c.2597dup (p.Pro867fs)	Likely pathogenic
501482	NM_004393.6(DAG1):c.41del (p.Ser14fs)	Likely pathogenic
817528	NM_004393.6(DAG1):c.556G>T (p.Glu186Ter)	Likely pathogenic

SpliceAI

1126 predictions. Top by Δscore:

Variant	Effect	Δscore
3:49510415:TCAG:T	acceptor_loss	1.0000
3:49510416:CAGGC:C	acceptor_loss	1.0000
3:49510417:A:AG	acceptor_gain	1.0000
3:49510418:G:GG	acceptor_gain	1.0000
3:49510418:GGCT:G	acceptor_gain	1.0000
3:49510418:GGCTC:G	acceptor_gain	1.0000
3:49476659:T:A	acceptor_gain	0.9900
3:49510417:AG:A	acceptor_gain	0.9900
3:49510418:GG:G	acceptor_gain	0.9900
3:49510418:GGC:G	acceptor_gain	0.9900
3:49510816:CAAG:C	donor_loss	0.9900
3:49510817:AAGGT:A	donor_loss	0.9900
3:49510818:AGG:A	donor_loss	0.9900
3:49510821:T:G	donor_loss	0.9900
3:49510848:G:GT	donor_gain	0.9900
3:49471050:G:GG	donor_gain	0.9800
3:49471046:C:G	donor_gain	0.9700
3:49497991:A:G	donor_gain	0.9700
3:49471046:C:CG	donor_gain	0.9600
3:49530791:TTCTA:T	acceptor_loss	0.9600
3:49530793:CTAG:C	acceptor_loss	0.9600
3:49530794:TAG:T	acceptor_loss	0.9600
3:49530795:AGG:A	acceptor_loss	0.9600
3:49476665:T:TA	acceptor_gain	0.9500
3:49510416:CAGG:C	acceptor_gain	0.9500
3:49470434:G:GG	donor_gain	0.9400
3:49476666:G:A	acceptor_gain	0.9400
3:49481998:T:G	donor_gain	0.9400
3:49510415:TCAGG:T	acceptor_gain	0.9400
3:49510418:G:T	acceptor_gain	0.9400

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000013805 (3:49532566 T>C), RS1000035625 (3:49535943 A>G), RS1000049694 (3:49470080 G>A), RS1000092741 (3:49514436 A>G), RS1000122403 (3:49529471 A>G), RS1000218345 (3:49493462 A>G), RS1000310453 (3:49526426 T>G), RS1000340719 (3:49499772 G>A), RS1000358023 (3:49476195 T>G), RS1000360067 (3:49494896 G>C), RS1000434111 (3:49500190 T>C), RS1000446422 (3:49487557 C>T), RS1000493121 (3:49491633 C>T), RS1000499084 (3:49480529 G>A), RS1000526650 (3:49514802 CAT>C,CATAT)

Disease associations

OMIM: gene MIM:128239 | disease phenotypes: MIM:613818, MIM:616538, MIM:609049, MIM:249660, MIM:614199, MIM:236670

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive limb-girdle muscular dystrophy type 2P	Definitive	Autosomal recessive
muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9	Definitive	Autosomal recessive
neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan	Strong	Autosomal recessive
muscular dystrophy-dystroglycanopathy, type A	Supportive	Autosomal recessive
isolated asymptomatic elevation of creatine phosphokinase	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan	Definitive	AR

Mondo (9): autosomal recessive limb-girdle muscular dystrophy type 2P (MONDO:0013440), muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9 (MONDO:0014683), neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan (MONDO:0018282), myopathy (MONDO:0005336), Pierson syndrome (MONDO:0012184), LAMB2-related infantile-onset nephrotic syndrome (MONDO:0013621), muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 (MONDO:0009364), isolated asymptomatic elevation of creatine phosphokinase (MONDO:0016103), muscular dystrophy-dystroglycanopathy, type A (MONDO:0000171)

Orphanet (7): Alpha-dystroglycan-related limb-girdle muscular dystrophy R16 (Orphanet:280333), Muscle-eye-brain disease with bilateral multicystic leucodystrophy (Orphanet:370997), Walker-Warburg syndrome (Orphanet:899), Qualitative or quantitative defects of alpha-dystroglycan (Orphanet:371024), Pierson syndrome (Orphanet:2670), LAMB2-related infantile-onset nephrotic syndrome (Orphanet:306507), Muscle-eye-brain disease (Orphanet:588)

HPO phenotypes

94 total (30 of 94 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000193	Bifid uvula
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000482	Microcornea
HP:0000501	Glaucoma
HP:0000518	Cataract
HP:0000528	Anophthalmia
HP:0000541	Retinal detachment
HP:0000556	Retinal dystrophy
HP:0000557	Buphthalmos
HP:0000568	Microphthalmia
HP:0000587	Abnormal optic nerve morphology
HP:0000612	Iris coloboma
HP:0000648	Optic atrophy
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001270	Motor delay

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST003097_9	Pediatric autoimmune diseases	8.000000e-11
GCST003818_48	Resting heart rate	3.000000e-13
GCST003854_53	Gut microbiota (functional units)	4.000000e-06
GCST004131_23	Inflammatory bowel disease	1.000000e-33
GCST004132_17	Crohn’s disease	3.000000e-23
GCST004133_11	Ulcerative colitis	8.000000e-20
GCST005316_124	Intelligence (MTAG)	4.000000e-11
GCST005951_49	Body mass index	1.000000e-08
GCST006922_9	Regular attendance at a religious group	3.000000e-08
GCST007044_11	Extremely high intelligence	4.000000e-08
GCST007559_24	Sleep duration (short sleep)	3.000000e-08
GCST008058_211	Estimated glomerular filtration rate	1.000000e-12
GCST008059_182	Estimated glomerular filtration rate	1.000000e-12
GCST008357_20	Mood instability	4.000000e-11
GCST010002_422	Refractive error	4.000000e-14
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13
GCST90002400_359	Plateletcrit	9.000000e-11
GCST90020024_1144	A body shape index	2.000000e-09
GCST90020029_1175	Waist circumference adjusted for body mass index	1.000000e-13

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0004337	intelligence
EFO:0004340	body mass index
EFO:0009592	social interaction measurement
EFO:0008475	mood instability measurement
EFO:0004346	neuroimaging measurement
EFO:0007985	platelet crit
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D058494	Walker-Warburg Syndrome	C10.500.507.450.499.249.500; C11.270.881; C16.131.666.507.450.499.249.500; C16.320.577.750
C565405	Mesangial Sclerosis, Diffuse Renal, with Ocular Abnormalities (supp.)
C537185	Pierson syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3714399 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression, affects expression	5
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	5
Benzo(a)pyrene	decreases methylation, affects methylation, decreases expression	3
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	3
trichostatin A	affects cotreatment, increases expression	2
Air Pollutants	affects cotreatment, decreases expression, increases abundance	2
Arsenic	affects cotreatment, decreases expression, increases abundance	2
Cadmium	increases expression, decreases expression, increases abundance	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects cotreatment, decreases expression, decreases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
deoxynivalenol	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	decreases methylation, increases methylation	1
aflatoxin B2	increases methylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects expression, affects reaction	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3744304	Binding	Increase of functional O-mannosylation of alpha-dystroglycan in human myotubes expressing myogenin after 48 hrs by alpha-screen assay	Small molecules enhance functional O-mannosylation of Alpha-dystroglycan. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2VJ	Abcam HEK293T DAG1 KO	Transformed cell line	Female
CVCL_SK29	HAP1 DAG1 (-) 1	Cancer cell line	Male
CVCL_SK30	HAP1 DAG1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120055	PHASE4	COMPLETED	Association Between Systemic Exposure of Atorvastatin and Metabolites and Atorvastatin-induced Myotoxicity
NCT03633565	PHASE4	UNKNOWN	Comparative Study of Strategies for Management of Duchenne Myopathy (DM)
NCT01225614	PHASE3	UNKNOWN	Efficacy and Tolerance of Early Launching of Nocturnal Non Invasive
NCT00278564	PHASE1	TERMINATED	Stem Cell Transplantation in Idiopathic Inflammatory Myopathy Diseases
NCT05989620	Not specified	RECRUITING	Long-Term Development of Muscular Dystrophy Outcome Assessments
NCT04001595	Not specified	UNKNOWN	Global FKRP Registry
NCT01403402	Not specified	RECRUITING	Congenital Muscle Disease Study of Patient and Family Reported Medical Information
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT02124070	PHASE1/PHASE2	WITHDRAWN	Therapeutic Effect of Recombinant Human Growth Hormone (rhGH) on the Myopathy of Cystinosis
NCT00549029	Not specified	UNKNOWN	The Association of Genetic Polymorphisms With Statin-Induced Myopathy.
NCT00767130	Not specified	UNKNOWN	DNA Diagnostic System for Statin Safety and Efficacy
NCT00922428	Not specified	COMPLETED	PASCOE-Agil HOM-Injektopas in the Treatment of Rheumatic Disorders
NCT00937001	Not specified	ACTIVE_NOT_RECRUITING	Critical Illness Myopathy as a Cause of Debilitating ICU-Acquired Weakness
NCT00990834	Not specified	WITHDRAWN	Muscle Characteristics Associated With Statin Therapy
NCT01022450	Not specified	UNKNOWN	Study of the Causes of the Breakdown of Muscle Fibers in Hospitalized Patients
NCT01040650	Not specified	TERMINATED	Metabolic Features of Post-Myopathy Patients Associated With Statin Treatment
NCT01047163	Not specified	COMPLETED	Maintenance of Muscle Mass in Older People: the Negative Impact of Statin Therapy
NCT01270269	Not specified	COMPLETED	ACT-ICU Study: Activity and Cognitive Therapy in the Intensive Care Unit
NCT01353430	Not specified	RECRUITING	Characterization of Inclusion Body Myopathy Associated With Paget’s Disease of Bone and Frontotemporal Dementia (IBMPFD)
NCT01395563	Not specified	WITHDRAWN	Strength Training on Pancreatic Cancer
NCT01530841	Not specified	COMPLETED	Efficacy and Tolerance of AVAPS Mode in Myotonic Dystrophy
NCT01547767	Not specified	COMPLETED	Investigations Into ISCU Myopathy or Iron Sulfur Scaffold U Protein Myopathy
NCT01702987	Not specified	COMPLETED	Evaluation of Ubiquinol on Mitochondrial Oxidative Capacity in Statin Patients Using 31PMRS
NCT01790178	Not specified	COMPLETED	Ultrasound in Muscle Biopsy
NCT02011282	Not specified	COMPLETED	Electro-Neuro-Muscular Stimulation in ICU
NCT02104921	Not specified	COMPLETED	Innovative Ultrasound Technology in Neuromuscular Disease
NCT02118805	Not specified	COMPLETED	Innovative Measures of Speech and Swallowing Dysfunction in Neurological Disorders
NCT02235220	Not specified	UNKNOWN	Reduction of Masticatory Muscle Activity by Restoring Canine Guidance
NCT02247895	Not specified	TERMINATED	Treatment of Muscle Weakness in Critically Ill Patients
NCT02315339	Not specified	TERMINATED	European Home Mechanical Ventilation Registry
NCT02442986	Not specified	COMPLETED	Neurological Outcome in Surgical and Non-surgical Septic Patients
NCT02706314	Not specified	COMPLETED	Impact of Human Blood Serum From Critically Ill Patients on Human Colon Neuronal Networks.
NCT02765828	Not specified	COMPLETED	Identification of Tongue Involvement in Late-Onset Pompe Disease
NCT03042286	Not specified	UNKNOWN	SAPhIRE Statin Adverse Drug Reaction
NCT03141749	Not specified	COMPLETED	Venous Thromboembolism in DM1
NCT03660969	Not specified	ACTIVE_NOT_RECRUITING	Reliability of Cardiac Troponins for the Diagnosis of Myocardial Infarction in the Presence of Skeletal Muscle Disease
NCT03749538	Not specified	RECRUITING	Acute Transcranial Direct Current Stimulation in Patients With Systemic Autoimmune Myopathies
NCT03751644	Not specified	COMPLETED	Peripherical Neuromuscular Electrical Stimulation in Systemic Autoimmune Myopathies
NCT03998540	Not specified	UNKNOWN	Improvement of DIAgnostic and Phenotype-genotype Correlation Studies in Patients With MYOpathy Suspected of TITinopathy
NCT04678635	Not specified	RECRUITING	Chronic Transcranial Direct Current Stimulation in Patients With Systemic Autoimmune Myopathies