Neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan

Summary

Neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan (MONDO:0018282) is a disease caused by DAG1 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Causal gene: DAG1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 1
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan
Mondo ID	MONDO:0018282
Orphanet	371024
UMLS	C2936406
MedGen	423526
GARD	0021601
Is cancer (heuristic)	no

Also known as: alpha-dystroglycanopathy · dystroglycanopathy · qualitative or quantitative defects of alpha-dystroglycan

Data availability: 1 ClinVar variant · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › qualitative or quantitative protein defects in neuromuscular diseases › neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan

Related subtypes (18): sarcoglycanopathy, neuromuscular disease caused by qualitative or quantitative defects of dysferlin, caveolinopathy, neuromuscular disease caused by qualitative or quantitative defects of dystrophin, neuromuscular disease caused by qualitative or quantitative defects of perlecan, neuromuscular disease caused by qualitative or quantitative defects of TRIM32, neuromuscular disease caused by qualitative or quantitative defects of myofibrillar proteins, neuromuscular disease caused by qualitative or quantitative defects of titin, neuromuscular disease caused by qualitative or quantitative defects of telethonin, neuromuscular disease caused by qualitative or quantitative defects of alpha-actin, neuromuscular disease caused by qualitative or quantitative defects of nebulin, neuromuscular disease caused by qualitative or quantitative defects of beta-myosin heavy chain (MYH7), neuromuscular disease caused by qualitative or quantitative defects of selenoprotein N1, neuromuscular disease caused by qualitative or quantitative defects of plectin, neuromuscular disease caused by qualitative or quantitative defects of protein SERCA1, neuromuscular disease caused by qualitative or quantitative defects of tropomyosin, alpha-actinopathy, collagen 6-related myopathy

Subtypes (1): qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
285302	NM_004393.6(DAG1):c.1954C>T (p.Arg652Trp)	DAG1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
DAG1	Strong	Autosomal recessive	neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DAG1	Orphanet:206599	Isolated asymptomatic elevation of creatine phosphokinase
DAG1	Orphanet:280333	Alpha-dystroglycan-related limb-girdle muscular dystrophy R16
DAG1	Orphanet:370997	Muscle-eye-brain disease with bilateral multicystic leucodystrophy
DAG1	Orphanet:899	Walker-Warburg syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DAG1	HGNC:2666	ENSG00000173402	Q14118	Dystroglycan 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DAG1	Dystroglycan 1	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 my…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DAG1	Antibody/Immunoglobulin	yes		Cadg, DAG1_C, Ig-like_fold

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal root ganglion	1
olfactory bulb	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DAG1	299	ubiquitous	marker	olfactory bulb, trigeminal ganglion, dorsal root ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DAG1	2,301

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DAG1	Q14118	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective POMGNT1 causes MDDGA3, MDDGB3 and MDDGC3	1	5710.0×	0.001	DAG1
Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2	1	3806.7×	0.001	DAG1
Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1	1	3806.7×	0.001	DAG1
DAG1 core M1 glycosylations	1	2855.0×	0.001	DAG1
DAG1 core M2 glycosylations	1	2284.0×	0.001	DAG1
DAG1 core M3 glycosylations	1	1903.3×	0.001	DAG1
Matriglycan biosynthesis on DAG1	1	815.7×	0.002	DAG1
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	368.4×	0.004	DAG1
Formation of the dystrophin-glycoprotein complex (DGC)	1	308.6×	0.004	DAG1
Non-integrin membrane-ECM interactions	1	154.3×	0.007	DAG1
ECM proteoglycans	1	150.3×	0.007	DAG1
Regulation of expression of SLITs and ROBOs	1	69.2×	0.014	DAG1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
muscle attachment	1	16852.0×	0.001	DAG1
nerve maturation	1	16852.0×	0.001	DAG1
calcium-dependent cell-matrix adhesion	1	8426.0×	0.001	DAG1
retrograde trans-synaptic signaling by trans-synaptic protein complex	1	5617.3×	0.002	DAG1
response to denervation involved in regulation of muscle adaptation	1	2407.4×	0.002	DAG1
morphogenesis of an epithelial sheet	1	1685.2×	0.002	DAG1
angiogenesis involved in wound healing	1	1685.2×	0.002	DAG1
branching involved in salivary gland morphogenesis	1	1404.3×	0.002	DAG1
microtubule anchoring	1	1296.3×	0.002	DAG1
axon regeneration	1	1123.5×	0.002	DAG1
commissural neuron axon guidance	1	991.3×	0.002	DAG1
nerve development	1	936.2×	0.002	DAG1
myelination in peripheral nervous system	1	887.0×	0.002	DAG1
skeletal muscle tissue regeneration	1	887.0×	0.002	DAG1
regulation of neurotransmitter receptor localization to postsynaptic specialization membrane	1	887.0×	0.002	DAG1
epithelial tube branching involved in lung morphogenesis	1	842.6×	0.002	DAG1
cellular response to cholesterol	1	842.6×	0.002	DAG1
positive regulation of myelination	1	766.0×	0.002	DAG1
positive regulation of cell-matrix adhesion	1	674.1×	0.002	DAG1
positive regulation of oligodendrocyte differentiation	1	674.1×	0.002	DAG1
membrane protein ectodomain proteolysis	1	648.1×	0.002	DAG1
positive regulation of Rac protein signal transduction	1	648.1×	0.002	DAG1
regulation of synapse organization	1	648.1×	0.002	DAG1
inhibitory synapse assembly	1	624.1×	0.002	DAG1
response to muscle activity	1	581.1×	0.003	DAG1
basement membrane organization	1	510.7×	0.003	DAG1
response to peptide hormone	1	391.9×	0.003	DAG1
heart morphogenesis	1	374.5×	0.004	DAG1
morphogenesis of an epithelium	1	343.9×	0.004	DAG1
negative regulation of MAPK cascade	1	300.9×	0.004	DAG1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DAG1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DAG1	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	DAG1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DAG1	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01403402	Not specified	RECRUITING	Congenital Muscle Disease Study of Patient and Family Reported Medical Information