Dystroglycanopathy is a group of autosomal recessive muscular dystrophies caused by defective O-mannosyl glycosylation of alpha-dystroglycan (alpha-DG). At least 18 genes encode enzymes in the alpha-DG glycosylation pathway; loss-of-function mutations in any of them reduce the ability of alpha-DG to bind extracellular matrix ligands (laminin, agrin, neurexin), disrupting the link between the cytoskeleton and basement membrane. The clinical spectrum is continuous, ranging from the most severe Walker-Warburg syndrome (type A, with cobblestone lissencephaly, eye malformations, and congenital muscular dystrophy) through intermediate congenital forms with intellectual disability (type B) to milder limb-girdle muscular dystrophy (type C). Severity correlates with residual enzyme activity and degree of alpha-DG hypoglycosylation. The same gene can cause any severity type depending on the nature of the mutations.
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name: Dystroglycanopathy
creation_date: "2026-03-07T12:00:00Z"
updated_date: "2026-05-19T05:26:15Z"
category: Mendelian
synonyms:
- muscular dystrophy-dystroglycanopathy
- alpha-dystroglycanopathy
- dystroglycanopathy spectrum disorder
description: >
Dystroglycanopathy is a group of autosomal recessive muscular dystrophies caused by
defective O-mannosyl glycosylation of alpha-dystroglycan (alpha-DG). At least 18 genes
encode enzymes in the alpha-DG glycosylation pathway; loss-of-function mutations in any
of them reduce the ability of alpha-DG to bind extracellular matrix ligands (laminin,
agrin, neurexin), disrupting the link between the cytoskeleton and basement membrane.
The clinical spectrum is continuous, ranging from the most severe Walker-Warburg syndrome
(type A, with cobblestone lissencephaly, eye malformations, and congenital muscular
dystrophy) through intermediate congenital forms with intellectual disability (type B)
to milder limb-girdle muscular dystrophy (type C). Severity correlates with residual
enzyme activity and degree of alpha-DG hypoglycosylation. The same gene can cause any
severity type depending on the nature of the mutations.
disease_term:
preferred_term: dystroglycanopathy
term:
id: MONDO:0018276
label: muscular dystrophy-dystroglycanopathy
parents:
- Congenital muscular dystrophy
- Glycosylation disorder
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >
All dystroglycanopathies follow autosomal recessive inheritance. Affected
individuals carry biallelic mutations (homozygous or compound heterozygous)
in one of at least 18 causative genes.
prevalence:
- population: UK genetically confirmed congenital muscular dystrophy cohort
percentage: 26.5% of CMD cases
notes: >-
Stable population-wide prevalence estimates are not available in PubMed
abstracts for the whole dystroglycanopathy spectrum, but dystroglycanopathy
was the second most common subtype in a large UK CMD cohort.
evidence:
- reference: PMID:28688748
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Between 2001 and 2013, a genetically confirmed diagnosis of CMD was
obtained for 249 unrelated individuals referred to these services. The
most common CMD subtype was laminin-α2 related CMD (also known as MDC1A,
37.4%), followed by dystroglycanopathies (26.5%), Ullrich-CMD (15.7%),
SEPN1 (11.65%) and LMNA (8.8%) gene related CMDs.
explanation: >-
This UK cohort provides a quantitative estimate of the relative
prevalence of dystroglycanopathy within genetically confirmed CMD.
- population: Chinese congenital muscular dystrophy cohort
percentage: 21.0% of CMD cases
notes: >-
A large Chinese CMD epidemiology study similarly found alpha-
dystroglycanopathy in about one-fifth of genetically characterized CMD
cases.
evidence:
- reference: PMID:31066047
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most common forms identified were LAMA2-related CMD (36.4%),
followed by COL6-related CMD (23.2%) and α-dystroglycanopathy (21.0%).
The forms of CMD related to mutations in LMNA and SEPN1 were less
frequent (12.5% and 2.4%, respectively).
explanation: >-
This nationwide Chinese CMD cohort independently supports
dystroglycanopathy as a major but still rare CMD subgroup.
has_subtypes:
# Clinical severity classification
- name: Type A (Walker-Warburg syndrome / Muscle-Eye-Brain disease)
classification: clinical_severity
description: >
Most severe form with congenital muscular dystrophy, cobblestone lissencephaly,
and eye anomalies. Near-complete loss of alpha-DG glycosylation. Typically fatal
in the first years of life. Any of the 14 MDDG genes can cause type A when
both alleles are severely hypomorphic or null.
subtype_term:
preferred_term: muscular dystrophy-dystroglycanopathy type A
term:
id: MONDO:0000171
label: muscular dystrophy-dystroglycanopathy, type A
evidence:
- reference: PMID:31311558
reference_title: "Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
patients with a severe WWS manifestation predominantly present with profound
neonatal muscular hypotonia and a severe and progressive hydrocephalus with
involvement of brainstem and/or cerebellum
explanation: >-
Clinical characterization of severe type A (WWS) phenotype in a large
POMT1 cohort.
- name: Type B (Congenital muscular dystrophy with intellectual disability)
classification: clinical_severity
description: >
Intermediate form with congenital muscular dystrophy and variable intellectual
disability. Structural brain abnormalities may be present but are less severe
than type A. Eye involvement is variable. Patients retain some residual
enzyme activity from at least one allele.
subtype_term:
preferred_term: muscular dystrophy-dystroglycanopathy type B
term:
id: MONDO:0000172
label: muscular dystrophy-dystroglycanopathy, type B
- name: Type C (Limb-girdle muscular dystrophy)
classification: clinical_severity
description: >
Mildest form presenting as limb-girdle muscular dystrophy with onset in childhood
or adulthood. Brain and eye involvement are generally absent. Some residual
alpha-DG glycosylation is preserved. Substantial residual enzyme activity
permits partial matriglycan synthesis.
subtype_term:
preferred_term: muscular dystrophy-dystroglycanopathy type C
term:
id: MONDO:0000173
label: muscular dystrophy-dystroglycanopathy, type C
evidence:
- reference: PMID:31311558
reference_title: "Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The milder LGMD phenotypes constantly show markedly elevated creatine kinase
values in combination with microcephaly and cognitive impairment
explanation: >-
Even milder type C (LGMD) phenotypes from POMT1 mutations show elevated CK
with some cognitive involvement, confirming the continuous spectrum.
# Gene classification - one entry per causative gene
- name: MDDG1 (POMT1)
classification: gene
description: >-
POMT1 encodes protein O-mannosyltransferase 1, catalyzing the first step of
alpha-DG O-mannosylation in complex with POMT2. Biallelic truncating mutations
cause type A (WWS); at least one missense allele with residual activity causes
milder type B or C. Most common cause of type A dystroglycanopathy.
Documented severity types: A1, B1, C1.
genes:
- preferred_term: POMT1
term:
id: hgnc:9202
label: POMT1
evidence:
- reference: PMID:31311558
reference_title: "Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The phenotypic severity of POMT1-related dystroglycanopathies depends on
the residual enzyme activity. A genotype-phenotype correlation can be
assumed
explanation: >-
Large clinical cohort demonstrating genotype-phenotype correlation based
on residual POMT1 enzyme activity across the full A1/B1/C1 spectrum.
- name: MDDG2 (POMT2)
classification: gene
description: >-
POMT2 forms an obligate heterodimer with POMT1 for O-mannosylation initiation.
Mutations cause the full severity spectrum. POMT2 mutations are the second most
common cause of type A dystroglycanopathy after POMT1.
Documented severity types: A2, B2, C2.
genes:
- preferred_term: POMT2
term:
id: hgnc:19743
label: POMT2
- name: MDDG3 (POMGNT1)
classification: gene
description: >-
POMGNT1 catalyzes addition of GlcNAc to O-mannose in the M1 glycan branch.
Originally identified as the gene for muscle-eye-brain disease (MEB), a
Finnish founder mutation disorder. Can cause all three severity types.
Documented severity types: A3, B3, C3.
genes:
- preferred_term: POMGNT1
term:
id: hgnc:19139
label: POMGNT1
- name: MDDG4 (FKTN)
classification: gene
description: >-
Fukutin transfers the first ribitol-phosphate onto the core M3 glycan.
Originally identified as the gene for Fukuyama congenital muscular dystrophy
(FCMD), the most common muscular dystrophy in Japan due to a founder
retrotransposon insertion. Can cause all three severity types.
Documented severity types: A4, B4, C4.
genes:
- preferred_term: FKTN
term:
id: hgnc:3622
label: FKTN
evidence:
- reference: PMID:29081423
reference_title: "Muscular Dystrophy with Ribitol-Phosphate Deficiency: A Novel Post-Translational Mechanism in Dystroglycanopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
fukutin and FKRP transfer ribitol-phosphate onto sugar chains of
alpha-dystroglycan, and ISPD synthesizes CDP-ribitol, a donor substrate
for fukutin and FKRP
explanation: >-
Establishes the enzymatic function of fukutin as a ribitol-phosphate
transferase in the alpha-DG glycosylation pathway.
- name: MDDG5 (FKRP)
classification: gene
description: >-
FKRP transfers the second ribitol-phosphate. The most common cause of
dystroglycanopathy in European populations. The L276I founder mutation is
associated with milder LGMD2I (type C5) phenotype and is the most prevalent
FKRP allele. Severity ranges from WWS to adult-onset LGMD. Primary target
for ribitol supplementation therapy and AAV gene therapy.
Documented severity types: A5, B5, C5.
genes:
- preferred_term: FKRP
term:
id: hgnc:17997
label: FKRP
evidence:
- reference: DOI:10.3233/jnd-230205
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Missense point mutations in the Fukutin-related protein (FKRP) gene cause
variable reduction in the synthesis of matriglycan on alpha-dystroglycan
(α-DG) and a wide range of disease severity
explanation: >-
FKRP mutations cause variable matriglycan reduction and a wide severity
spectrum from WWS to LGMD.
- name: MDDG6 (LARGE1)
classification: gene
description: >-
LARGE1 is the bifunctional xylosyl- and glucuronyltransferase that polymerizes
the terminal matriglycan repeat on alpha-DG. Mutations can cause all three
severity types. LARGE1 overexpression has been explored as a therapeutic
strategy for multiple dystroglycanopathies.
Documented severity types: A6, B6, C6.
genes:
- preferred_term: LARGE1
term:
id: hgnc:6511
label: LARGE1
evidence:
- reference: DOI:10.7554/eLife.82811
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
is uniquely synthesized on α-dystroglycan (α-DG) by
like-acetylglucosaminyltransferase-1 (LARGE1)
explanation: >-
Identifies LARGE1 as the enzyme that synthesizes matriglycan on alpha-DG.
- name: MDDG7 (CRPPA)
classification: gene
description: >-
CRPPA (formerly ISPD) synthesizes CDP-ribitol, the donor substrate for
fukutin and FKRP. Mutations cause severe type A and milder type C phenotypes.
No type B cases have been formally classified.
Documented severity types: A7, C7.
genes:
- preferred_term: CRPPA
term:
id: hgnc:37276
label: CRPPA
evidence:
- reference: PMID:29081423
reference_title: "Muscular Dystrophy with Ribitol-Phosphate Deficiency: A Novel Post-Translational Mechanism in Dystroglycanopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
ISPD synthesizes CDP-ribitol, a donor substrate for fukutin and FKRP
explanation: >-
Identifies CRPPA/ISPD as the CDP-ribitol synthase essential for the
ribitol-phosphate pathway.
- name: MDDG8 (POMGNT2)
classification: gene
description: >-
POMGNT2 adds GlcNAc to O-mannose in the core M3 glycan branch, initiating
the pathway that leads to matriglycan. Mutations predominantly cause severe
type A; milder type C (LGMD) cases have also been reported.
Documented severity types: A8, C8.
genes:
- preferred_term: POMGNT2
term:
id: hgnc:25902
label: POMGNT2
- name: MDDG9 (DAG1)
classification: gene
description: >-
DAG1 encodes dystroglycan itself. Rare missense mutations in the mucin-like
domain of alpha-DG disrupt glycosylation sites, causing primary
dystroglycanopathy. One of the rarest forms. Can cause type A or type C.
Documented severity types: A9, C9.
genes:
- preferred_term: DAG1
term:
id: hgnc:2666
label: DAG1
- name: MDDG10 (RXYLT1)
classification: gene
description: >-
RXYLT1 (formerly TMEM5) is a xylosyltransferase involved in the linker
region between core M3 and matriglycan. Mutations cause predominantly
severe type A phenotypes. Very rare.
Documented severity types: A10.
genes:
- preferred_term: RXYLT1
term:
id: hgnc:13530
label: RXYLT1
- name: MDDG11 (B3GALNT2)
classification: gene
description: >-
B3GALNT2 adds GalNAc to the core M3 glycan. Mutations cause predominantly
severe type A phenotypes with cobblestone lissencephaly and eye anomalies.
Very rare.
Documented severity types: A11.
genes:
- preferred_term: B3GALNT2
term:
id: hgnc:28596
label: B3GALNT2
- name: MDDG12 (POMK)
classification: gene
description: >-
POMK phosphorylates O-mannose on the core M3 glycan, a prerequisite for
LARGE1 to extend matriglycan to full length. Mutations cause type A and
milder LGMD phenotypes.
Documented severity types: A12, C12.
genes:
- preferred_term: POMK
term:
id: hgnc:26267
label: POMK
evidence:
- reference: DOI:10.7554/eLife.82811
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
-mannose kinase (POMK) is required for LARGE1 to generate full-length
matriglycan on α-DG (~150–250 kDa)
explanation: >-
Demonstrates that POMK-mediated phosphorylation is a prerequisite for
full matriglycan extension by LARGE1.
- name: MDDG13 (B4GAT1)
classification: gene
description: >-
B4GAT1 (formerly B3GNT1) is a glucuronyltransferase that adds the priming
glucuronic acid in the linker region, initiating LARGE1-mediated matriglycan
polymerization. Mutations cause severe type A phenotypes. Very rare.
Documented severity types: A13.
genes:
- preferred_term: B4GAT1
term:
id: hgnc:15685
label: B4GAT1
- name: MDDG14 (GMPPB)
classification: gene
description: >-
GMPPB synthesizes GDP-mannose, the sugar donor for POMT1/POMT2-mediated
O-mannosylation. Mutations cause the full severity spectrum. Milder forms
may present with congenital myasthenic syndrome-like features with
fatigable weakness, in addition to dystrophic changes.
Documented severity types: A14, B14, C14.
genes:
- preferred_term: GMPPB
term:
id: hgnc:22932
label: GMPPB
- name: DPM1-related dystroglycanopathy
classification: gene
description: >-
DPM1 encodes the catalytic subunit of dolichol-phosphate mannose synthase,
which provides the mannose donor for multiple glycosylation pathways including
O-mannosylation of alpha-DG. Mutations cause congenital disorder of
glycosylation (CDG) with secondary dystroglycanopathy features. Phenotype
includes muscular dystrophy, seizures, and intellectual disability, often
with additional CDG features such as coagulopathy. Not assigned a formal
MDDG number as the primary classification is CDG (DPM1-CDG).
genes:
- preferred_term: DPM1
term:
id: hgnc:3005
label: DPM1
- name: DPM2-related dystroglycanopathy
classification: gene
description: >-
DPM2 encodes a regulatory subunit of dolichol-phosphate mannose synthase.
Mutations cause CDG with secondary dystroglycanopathy. Extremely rare with
very few reported patients. Clinical features include severe muscular
dystrophy, seizures, and intellectual disability with broader CDG
manifestations. Not assigned a formal MDDG number (DPM2-CDG).
genes:
- preferred_term: DPM2
term:
id: hgnc:3006
label: DPM2
- name: DPM3-related dystroglycanopathy
classification: gene
description: >-
DPM3 encodes a stabilizing subunit of dolichol-phosphate mannose synthase.
Mutations cause CDG with secondary dystroglycanopathy. Extremely rare.
Phenotype includes muscular dystrophy with dilated cardiomyopathy as a
distinguishing feature. Not assigned a formal MDDG number (DPM3-CDG).
genes:
- preferred_term: DPM3
term:
id: hgnc:3007
label: DPM3
pathophysiology:
- name: Defective alpha-dystroglycan O-mannosyl glycosylation
description: >
The core mechanism shared by all dystroglycanopathies. Alpha-dystroglycan requires
extensive O-mannosyl glycosylation to generate matriglycan, a repeating disaccharide
polymer that serves as the laminin-binding moiety. At least 18 genes encode enzymes
in this sequential biosynthetic pathway: POMT1/POMT2 initiate O-mannosylation,
POMGNT2/B3GALNT2/POMK elaborate the core M3 glycan, FKTN/FKRP/CRPPA add
ribitol-phosphate linkers, and LARGE1 polymerizes the terminal matriglycan.
Mutations in any of these genes reduce or abolish matriglycan, preventing
alpha-DG from binding laminin, agrin, and other extracellular matrix proteins.
cell_types:
- preferred_term: skeletal muscle fiber
term:
id: CL:0008002
label: skeletal muscle fiber
biological_processes:
- preferred_term: protein O-linked mannosylation
term:
id: GO:0035269
label: protein O-linked glycosylation via mannose
evidence:
- reference: PMID:29081423
reference_title: "Muscular Dystrophy with Ribitol-Phosphate Deficiency: A Novel Post-Translational Mechanism in Dystroglycanopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Abnormal glycosylation of alpha-dystroglycan reduces its binding activities
to ligand proteins, including laminins
explanation: >-
Review establishing that defective alpha-DG glycosylation reduces laminin
binding as the common biochemical feature of all dystroglycanopathies.
- reference: PMID:29081423
reference_title: "Muscular Dystrophy with Ribitol-Phosphate Deficiency: A Novel Post-Translational Mechanism in Dystroglycanopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The normal sugar chain contains tandem structures of ribitol-phosphate, a
pentose alcohol that was previously unknown in humans. The dystroglycanopathy
genes fukutin, fukutin-related protein (FKRP), and isoprenoid synthase
domain-containing protein (ISPD) encode essential enzymes for the synthesis
of this structure
explanation: >-
Identifies the ribitol-phosphate pathway as a key component of the alpha-DG
glycosylation machinery, with FKTN, FKRP, and ISPD/CRPPA as essential enzymes.
- reference: DOI:10.7554/eLife.82811
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
a shorter form of matriglycan reduce the size of α-DG and decrease
laminin binding, leading to various forms of muscular dystrophy
explanation: >-
Demonstrates that matriglycan length is the key functional parameter
and that shortened matriglycan causes muscular dystrophy.
- reference: PMID:34884967
reference_title: "Dystroglycanopathy: From Elucidation of Molecular and Pathological Mechanisms to Development of Treatment Methods."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
At least 18 causative genes of dystroglycanopathy have been identified, and
its clinical symptoms are diverse, ranging from severe congenital to
adult-onset limb-girdle types
explanation: >-
Comprehensive review confirming 18+ causative genes and the continuous
severity spectrum of dystroglycanopathy.
downstream:
- target: Sarcolemmal fragility and progressive muscle degeneration
causal_link_type: DIRECT
description: >-
Shortened or absent matriglycan reduces alpha-dystroglycan size and
laminin binding, destabilizing the muscle membrane during contraction.
evidence:
- reference: DOI:10.7554/eLife.82811
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
-glycosylation of α-DG that result in a shorter form of matriglycan
reduce the size of α-DG and decrease laminin binding, leading to
various forms of muscular dystrophy.
explanation: >-
This model-organism study links defective alpha-DG glycosylation to
reduced laminin binding and muscular dystrophy.
- target: Glial limitans disruption and neuronal overmigration
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Loss of alpha-dystroglycan basement-membrane anchoring during cortical development.
description: >-
Severe dystroglycan glycosylation defects disrupt brain development,
consistent with the type A cortical malformation branch.
evidence:
- reference: PMID:26060116
reference_title: "Ectopic clustering of Cajal-Retzius and subplate cells is an initial pathological feature in Pomgnt2-knockout mice, a model of dystroglycanopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Aberrant glycosylation of dystroglycan causes congenital muscular
dystrophies associated with cobblestone lissencephaly, classified as
dystroglycanopathy.
explanation: >-
This model-organism study links aberrant dystroglycan glycosylation to
the cobblestone-lissencephaly brain branch of dystroglycanopathy.
- target: Inhibitory synapse dysfunction and seizure susceptibility
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Impaired CCK+/CB1R+ interneuron axon targeting and perisomatic inhibitory synapse assembly.
description: Severe dystroglycan glycosylation defects disrupt inhibitory synapse organization.
evidence:
- reference: DOI:10.7554/eLife.87965
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Collectively, these data show that inhibitory synaptic defects and
elevated seizure susceptibility are hallmarks of severe
dystroglycanopathy, and show that Dystroglycan plays an important role
in organizing functional inhibitory synapse assembly.
explanation: >-
This directly supports the inhibitory-synapse branch in severe
dystroglycanopathy.
- target: Retinal basement membrane disruption and eye malformations
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Loss of alpha-dystroglycan laminin binding at ocular basement membranes.
description: Severe alpha-DG glycosylation defects are associated with eye involvement in the dystroglycanopathy spectrum.
evidence:
- reference: PMID:16887026
reference_title: "Walker-Warburg syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
WWS presents at birth with generalized hypotonia, muscle weakness,
developmental delay with mental retardation and occasional seizures. It
is associated with type II cobblestone lissencephaly, hydrocephalus,
cerebellar malformations, eye abnormalities and congenital muscular
dystrophy characterized by hypoglycosylation of alpha-dystroglycan.
explanation: >-
This review supports eye abnormalities in severe Walker-Warburg/type A
dystroglycanopathy with alpha-dystroglycan hypoglycosylation.
- target: Dystroglycan as signaling hub
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Reduced ligand binding changes both mechanical adhesion and outside-inside dystroglycan signaling.
description: Defective alpha-DG glycosylation can perturb dystroglycan's broader adhesion-signaling role.
evidence:
- reference: DOI:10.3389/fmolb.2023.1325284
supports: SUPPORT
evidence_source: OTHER
snippet: >-
DG is a versatile molecule acting not only as a mechanical building
block but also as a modulator of outside–inside signaling events
explanation: >-
This review supports dystroglycan's dual mechanical and signaling role,
which can be affected when alpha-DG ligand binding is impaired.
- name: Sarcolemmal fragility and progressive muscle degeneration
description: >
Loss of alpha-DG-laminin binding disrupts the dystrophin-glycoprotein complex (DGC)
link between the intracellular cytoskeleton and the extracellular basement membrane.
This renders the sarcolemma mechanically fragile, leading to contraction-induced
damage, repeated cycles of muscle fiber necrosis and regeneration, progressive
fibrosis, and fatty replacement. This mechanism is common to all severity types
and underlies the progressive proximal muscular weakness and elevated serum
creatine kinase characteristic of the disease.
cell_types:
- preferred_term: skeletal muscle fiber
term:
id: CL:0008002
label: skeletal muscle fiber
locations:
- preferred_term: skeletal muscle tissue
term:
id: UBERON:0001134
label: skeletal muscle tissue
biological_processes:
- preferred_term: muscle contraction
term:
id: GO:0006936
label: muscle contraction
evidence:
- reference: DOI:10.7554/eLife.82811
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
This smaller form of α-DG binds laminin and maintains specific force but
does not prevent muscle pathophysiology, including reduced force production
after eccentric contractions (ECs) or abnormalities in the neuromuscular
junctions
explanation: >-
Mouse model demonstrates that shortened matriglycan preserves baseline force
but fails to protect against eccentric contraction-induced damage.
- reference: DOI:10.3389/fmolb.2023.1325284
supports: SUPPORT
evidence_source: OTHER
snippet: >-
represents a molecular bridge between the outside and the inside of the cell,
which is essential for the mechanical and structural stability of the plasma
membrane
explanation: >-
Review establishing dystroglycan as the critical mechanical link between
ECM and cytoskeleton for sarcolemmal stability.
downstream:
- target: Proximal muscle weakness
causal_link_type: DIRECT
description: Progressive muscle fiber degeneration manifests as proximally pronounced weakness.
evidence:
- reference: PMID:31311558
reference_title: "Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
POMT1-related disorders belong to the group of dystroglycanopathies
characterized by a proximally pronounced muscular dystrophy with
structural or functional involvement of the brain and/or the eyes
explanation: >-
This human cohort supports proximal muscular dystrophy as a core
manifestation of the muscle degeneration branch.
- target: Muscular dystrophy
causal_link_type: DIRECT
description: Recurrent sarcolemmal damage produces the dystrophic muscle pathology shared across the spectrum.
evidence:
- reference: DOI:10.7554/eLife.82811
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
-glycosylation of α-DG that result in a shorter form of matriglycan
reduce the size of α-DG and decrease laminin binding, leading to
various forms of muscular dystrophy.
explanation: >-
This directly links reduced alpha-DG glycosylation and laminin binding
to muscular dystrophy.
- target: Elevated serum creatine kinase
causal_link_type: DIRECT
description: Active muscle fiber injury and degeneration produce elevated circulating creatine kinase.
evidence:
- reference: PMID:31311558
reference_title: "Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The milder LGMD phenotypes constantly show markedly elevated creatine
kinase values in combination with microcephaly and cognitive impairment
explanation: >-
The clinical cohort supports elevated CK in milder dystroglycanopathy
phenotypes with ongoing muscle disease.
- target: Neonatal hypotonia
causal_link_type: DIRECT
description: Severe congenital muscle involvement can present at birth with profound hypotonia.
evidence:
- reference: PMID:31311558
reference_title: "Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
patients with a severe WWS manifestation predominantly present with
profound neonatal muscular hypotonia
explanation: >-
The POMT1 cohort supports neonatal hypotonia as a severe muscle-branch
manifestation.
- name: Glial limitans disruption and neuronal overmigration
description: >
In the developing brain, alpha-DG in radial glial cells anchors to the pial
basement membrane via laminin binding, maintaining the integrity of the glial
limitans. Severe alpha-DG hypoglycosylation causes breaches in this barrier,
allowing neurons to overmigrate beyond the cortical surface, producing the
characteristic cobblestone lissencephaly (type II). This developmental defect
is irreversible and is the hallmark of type A dystroglycanopathy. Partial
glycosylation loss may cause milder brain malformations (type B) or spare
the brain entirely (type C), reflecting tissue-specific threshold effects.
cell_types:
- preferred_term: radial glial cell
term:
id: CL:0000681
label: radial glial cell
locations:
- preferred_term: cerebral cortex
term:
id: UBERON:0000956
label: cerebral cortex
biological_processes:
- preferred_term: neuron migration
term:
id: GO:0001764
label: neuron migration
evidence:
- reference: DOI:10.7554/eLife.87965
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
a type of congenital muscular dystrophy characterized by a wide range
of phenotypes including muscle weakness, brain defects, and cognitive
impairment
explanation: >-
Mouse models of dystroglycanopathy confirm brain involvement including
cortical malformations in severe forms.
downstream:
- target: Cobblestone lissencephaly
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Pial basement membrane disruption with abnormal neuronal migration.
description: Severe type A dystroglycanopathy brain malformation includes cobblestone lissencephaly.
evidence:
- reference: PMID:26060116
reference_title: "Ectopic clustering of Cajal-Retzius and subplate cells is an initial pathological feature in Pomgnt2-knockout mice, a model of dystroglycanopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Our findings demonstrate the initial pathological events in
dystroglycanopathy mice and contribute to our understanding of how
dystroglycan dysfunction affects brain development and progresses to
cobblestone lissencephaly.
explanation: >-
The Pomgnt2-knockout dystroglycanopathy model directly connects
dystroglycan dysfunction, disrupted brain development, and cobblestone
lissencephaly.
- target: Intellectual disability
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Structural brain developmental defects.
description: Dystroglycanopathy brain involvement can include cognitive impairment and intellectual disability.
evidence:
- reference: DOI:10.7554/eLife.87965
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
a type of congenital muscular dystrophy characterized by a wide range
of phenotypes including muscle weakness, brain defects, and cognitive
impairment
explanation: >-
This model evidence explicitly lists cognitive impairment with brain
defects in dystroglycanopathy.
- target: Hydrocephalus
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Severe WWS-pattern brainstem and cerebellar involvement.
description: Severe type A disease can include progressive hydrocephalus.
evidence:
- reference: PMID:31311558
reference_title: "Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a severe and progressive hydrocephalus with involvement of brainstem
and/or cerebellum
explanation: >-
The POMT1 clinical cohort supports progressive hydrocephalus in severe
WWS/type A disease.
- name: Inhibitory synapse dysfunction and seizure susceptibility
description: >
Beyond structural brain malformations, alpha-DG glycosylation plays a critical
role in organizing functional inhibitory synapses. In the hippocampus,
dystroglycan is required for CCK+/CB1R+ basket interneuron axon targeting and
perisomatic inhibitory synapse assembly. Severe hypoglycosylation disrupts
these inhibitory circuits, reducing GABAergic transmission and increasing
seizure susceptibility. This represents a distinct neurological mechanism
from cobblestone lissencephaly.
cell_types:
- preferred_term: GABAergic interneuron
term:
id: CL:0011005
label: GABAergic interneuron
locations:
- preferred_term: hippocampal formation
term:
id: UBERON:0002421
label: hippocampal formation
biological_processes:
- preferred_term: synapse assembly
term:
id: GO:0007416
label: synapse assembly
evidence:
- reference: DOI:10.7554/eLife.87965
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
these data show that inhibitory synaptic defects and elevated seizure
susceptibility are hallmarks of severe dystroglycanopathy, and show that
Dystroglycan plays an important role in organizing functional inhibitory
synapse assembly
explanation: >-
Establishes that inhibitory synapse dysfunction and seizure susceptibility
are core features of severe dystroglycanopathy pathophysiology.
downstream:
- target: Seizures
causal_link_type: DIRECT
description: Inhibitory synaptic defects increase seizure susceptibility.
evidence:
- reference: DOI:10.7554/eLife.87965
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
these data show that inhibitory synaptic defects and elevated seizure
susceptibility are hallmarks of severe dystroglycanopathy, and show that
Dystroglycan plays an important role in organizing functional inhibitory
synapse assembly
explanation: >-
The mouse-model study directly links inhibitory synaptic defects to
elevated seizure susceptibility.
- name: Retinal basement membrane disruption and eye malformations
description: >
Alpha-DG in the retinal inner limiting membrane binds laminin to maintain retinal
architecture during development. Severe alpha-DG hypoglycosylation disrupts this
basement membrane, causing retinal dysplasia, anterior chamber malformations, and
in the most severe cases microphthalmos. Like brain involvement, eye pathology
requires near-complete loss of glycosylation and is predominantly seen in type A.
locations:
- preferred_term: retina
term:
id: UBERON:0000966
label: retina
cell_types:
- preferred_term: Muller glia
term:
id: CL:0000636
label: Mueller cell
biological_processes:
- preferred_term: retina morphogenesis in camera-type eye
term:
id: GO:0060042
label: retina morphogenesis in camera-type eye
downstream:
- target: Retinal dysplasia
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Severe dystroglycanopathy eye involvement through defective basement-membrane organization.
description: Severe ocular involvement in dystroglycanopathy can include retinal dysplasia.
evidence:
- reference: PMID:12825057
reference_title: "Ocular findings in lissencephaly."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Ocular abnormalities included optic nerve hypoplasia and atrophy,
retinal dysplasia, retinal nonattachment, macular hypoplasia, anterior
segment malformation, and strabismus.
explanation: >-
This clinical lissencephaly cohort supports retinal dysplasia among
ocular abnormalities in the cobblestone/type II lissencephaly spectrum;
it is partial evidence for the severe dystroglycanopathy eye branch.
- name: Dystroglycan as signaling hub
description: >
Beyond its mechanical role, dystroglycan functions as a signaling hub. Ligand-bound
alpha-DG influences beta-DG cytodomain phosphorylation and adaptor recruitment,
modulating PI3K/AKT and ERK signaling pathways. This dual role implies that
dystroglycanopathies involve both mechanical failure and signaling dysregulation,
potentially contributing to impaired muscle regeneration and survival.
biological_processes:
- preferred_term: signal transduction
term:
id: GO:0007165
label: signal transduction
evidence:
- reference: DOI:10.3389/fmolb.2023.1325284
supports: SUPPORT
evidence_source: OTHER
snippet: >-
DG is a versatile molecule acting not only as a mechanical building block but
also as a modulator of outside–inside signaling events
explanation: >-
Review establishing the dual adhesion and signaling role of dystroglycan.
phenotypes:
- category: MUSCULOSKELETAL
name: Proximal muscle weakness
description: >
Progressive proximal muscular weakness is the universal feature across all
dystroglycanopathy types. In type A it presents as severe neonatal hypotonia,
while in type C it may not manifest until childhood or adulthood.
frequency: OBLIGATE
phenotype_term:
preferred_term: proximal muscle weakness
term:
id: HP:0003701
label: Proximal muscle weakness
evidence:
- reference: PMID:31311558
reference_title: "Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
POMT1-related disorders belong to the group of dystroglycanopathies
characterized by a proximally pronounced muscular dystrophy with
structural or functional involvement of the brain and/or the eyes
explanation: >-
Large clinical cohort confirms proximal muscular dystrophy as the
cardinal feature across the dystroglycanopathy spectrum.
- category: MUSCULOSKELETAL
name: Elevated serum creatine kinase
description: >
Markedly elevated serum CK levels reflect ongoing muscle fiber necrosis and
are consistently found across all severity types.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: elevated serum creatine kinase
term:
id: HP:0003236
label: Elevated circulating creatine kinase concentration
evidence:
- reference: PMID:31311558
reference_title: "Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The milder LGMD phenotypes constantly show markedly elevated creatine
kinase values in combination with microcephaly and cognitive impairment
explanation: >-
Even in the mildest LGMD phenotypes, CK is markedly elevated, confirming
this as a consistent feature across all severity types.
- category: NEUROLOGICAL
name: Cobblestone lissencephaly
description: >
Type II (cobblestone) lissencephaly is the hallmark brain malformation of
type A dystroglycanopathy, resulting from neuronal overmigration through
breached glial limitans.
frequency: OBLIGATE
notes: Specific to type A; absent in types B and C
phenotype_term:
preferred_term: cobblestone lissencephaly
term:
id: HP:0007260
label: Type II lissencephaly
evidence:
- reference: PMID:26060116
reference_title: "Ectopic clustering of Cajal-Retzius and subplate cells is an initial pathological feature in Pomgnt2-knockout mice, a model of dystroglycanopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Aberrant glycosylation of dystroglycan causes congenital muscular
dystrophies associated with cobblestone lissencephaly, classified as
dystroglycanopathy.
explanation: >-
The Pomgnt2-knockout mouse model supports cobblestone lissencephaly as a
dystroglycanopathy brain phenotype.
- category: NEUROLOGICAL
name: Intellectual disability
description: >
Profound intellectual disability is present in type A. Variable intellectual
disability occurs in type B, ranging from mild to severe. Type C patients
may have mild cognitive impairment or normal cognition.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: intellectual disability
term:
id: HP:0001249
label: Intellectual disability
- category: OPHTHALMOLOGICAL
name: Retinal dysplasia
description: >
Structural retinal abnormalities occur primarily in type A dystroglycanopathy
as a consequence of retinal inner limiting membrane disruption during development.
phenotype_term:
preferred_term: retinal dysplasia
term:
id: HP:0007973
label: Retinal dysplasia
evidence:
- reference: PMID:12825057
reference_title: "Ocular findings in lissencephaly."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Ocular abnormalities included optic nerve hypoplasia and atrophy, retinal
dysplasia, retinal nonattachment, macular hypoplasia, anterior segment
malformation, and strabismus.
explanation: >-
This clinical cohort supports retinal dysplasia as an ocular abnormality
in the cobblestone/type II lissencephaly spectrum relevant to severe
dystroglycanopathy.
- category: NEUROLOGICAL
name: Seizures
description: >
Epileptic seizures occur in type A and some type B patients. In addition to
structural cortical malformation, seizure susceptibility results from impaired
inhibitory synapse assembly involving CCK+/CB1R+ basket interneurons.
phenotype_term:
preferred_term: seizures
term:
id: HP:0001250
label: Seizure
evidence:
- reference: DOI:10.7554/eLife.87965
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
these data show that inhibitory synaptic defects and elevated seizure
susceptibility are hallmarks of severe dystroglycanopathy
explanation: >-
Mouse models demonstrate that seizure susceptibility in dystroglycanopathy
results from impaired inhibitory synapse formation.
- category: MUSCULOSKELETAL
name: Muscular dystrophy
description: >
Dystrophic changes on muscle biopsy with fiber size variation, necrosis,
and fibrosis are present across all types.
frequency: OBLIGATE
phenotype_term:
preferred_term: muscular dystrophy
term:
id: HP:0003560
label: Muscular dystrophy
- category: MUSCULOSKELETAL
name: Neonatal hypotonia
description: >
Severe neonatal hypotonia is a presenting feature of type A and some type B
dystroglycanopathies. In the most severe forms, infants are profoundly
hypotonic at birth.
frequency: FREQUENT
notes: Primarily in type A and severe type B
phenotype_term:
preferred_term: neonatal hypotonia
term:
id: HP:0001319
label: Neonatal hypotonia
evidence:
- reference: PMID:31311558
reference_title: "Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
patients with a severe WWS manifestation predominantly present with
profound neonatal muscular hypotonia
explanation: >-
Profound neonatal hypotonia is a defining feature of the severe WWS
(type A) phenotype.
- category: NEUROLOGICAL
name: Hydrocephalus
description: >
Progressive hydrocephalus is common in type A, particularly in Walker-Warburg
syndrome. May require ventriculoperitoneal shunting.
notes: Primarily in type A (Walker-Warburg syndrome)
phenotype_term:
preferred_term: hydrocephalus
term:
id: HP:0000238
label: Hydrocephalus
evidence:
- reference: PMID:31311558
reference_title: "Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a severe and progressive hydrocephalus with involvement of brainstem
and/or cerebellum
explanation: >-
Progressive hydrocephalus with brainstem and cerebellar involvement is
characteristic of type A (WWS).
biochemical:
- name: Reduced alpha-dystroglycan glycosylation
notes: >
The hallmark biochemical finding is reduced functional glycosylation of
alpha-dystroglycan, detectable by the IIH6C4 antibody which recognizes
the matriglycan epitope. Western blot shows reduced molecular weight of
alpha-DG (normally ~150-250 kDa in muscle) correlating with shortened
matriglycan chains.
readouts:
- target: Defective alpha-dystroglycan O-mannosyl glycosylation
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
interpretation: Reduced alpha-dystroglycan glycosylation directly reports the primary matriglycan biosynthesis defect.
evidence:
- reference: DOI:10.7554/eLife.82811
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
-mannose kinase (POMK) is required for LARGE1 to generate full-length
matriglycan on α-DG (~150–250 kDa)
explanation: >-
This supports alpha-DG matriglycan length as a readout of the
glycosylation pathway.
evidence:
- reference: DOI:10.7554/eLife.82811
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
-mannose kinase (POMK) is required for LARGE1 to generate full-length
matriglycan on α-DG (~150–250 kDa)
explanation: >-
Establishes that full-length matriglycan produces ~150-250 kDa alpha-DG,
and defects in the pathway reduce this molecular weight.
- name: Reduced laminin binding
notes: >
Alpha-DG from affected patients shows reduced or absent binding to laminin
and other LG-domain-containing ECM proteins. Laminin overlay assay on muscle
biopsy is a key diagnostic tool.
readouts:
- target: Defective alpha-dystroglycan O-mannosyl glycosylation
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
interpretation: Reduced laminin binding reports loss of functional alpha-DG matriglycan.
evidence:
- reference: PMID:29081423
reference_title: "Muscular Dystrophy with Ribitol-Phosphate Deficiency: A Novel Post-Translational Mechanism in Dystroglycanopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Abnormal glycosylation of alpha-dystroglycan reduces its binding
activities to ligand proteins, including laminins
explanation: >-
This directly supports laminin binding as a functional readout of
alpha-DG glycosylation status.
evidence:
- reference: PMID:29081423
reference_title: "Muscular Dystrophy with Ribitol-Phosphate Deficiency: A Novel Post-Translational Mechanism in Dystroglycanopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Abnormal glycosylation of alpha-dystroglycan reduces its binding activities
to ligand proteins, including laminins
explanation: >-
Confirms reduced laminin binding as the functional consequence of
defective alpha-DG glycosylation.
genetic:
- name: POMT1
gene_term:
preferred_term: POMT1
term:
id: hgnc:9202
label: POMT1
association: Causative
features: >
POMT1 encodes protein O-mannosyltransferase 1, catalyzing the first step of
alpha-DG O-mannosylation. Biallelic truncating mutations cause type A (WWS);
at least one missense mutation with residual activity causes milder type B or C.
evidence:
- reference: PMID:31311558
reference_title: "Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The phenotypic severity of POMT1-related dystroglycanopathies depends on
the residual enzyme activity. A genotype-phenotype correlation can be
assumed
explanation: >-
Large clinical cohort demonstrating genotype-phenotype correlation based
on residual POMT1 enzyme activity.
- reference: PMID:31311558
reference_title: "Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with two mutations leading to premature protein termination had a
WWS phenotype, while the presence of at least one missense mutation was
associated with milder phenotypes
explanation: >-
Two truncating mutations cause severe WWS, while missense mutations
with residual activity cause milder phenotypes.
- name: POMT2
gene_term:
preferred_term: POMT2
term:
id: hgnc:19743
label: POMT2
association: Causative
features: >
POMT2 forms a complex with POMT1 for O-mannosylation initiation. Mutations
cause the full severity spectrum from WWS to LGMD.
- name: POMGNT1
gene_term:
preferred_term: POMGNT1
term:
id: hgnc:19139
label: POMGNT1
association: Causative
features: >
POMGNT1 catalyzes addition of GlcNAc to O-mannose in the M1 branch pathway.
Originally identified as the muscle-eye-brain disease gene.
- name: FKTN
gene_term:
preferred_term: FKTN
term:
id: hgnc:3622
label: FKTN
association: Causative
features: >
Fukutin transfers the first ribitol-phosphate onto the core M3 glycan.
Originally identified as the Fukuyama congenital muscular dystrophy gene.
evidence:
- reference: PMID:29081423
reference_title: "Muscular Dystrophy with Ribitol-Phosphate Deficiency: A Novel Post-Translational Mechanism in Dystroglycanopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
fukutin and FKRP transfer ribitol-phosphate onto sugar chains of
alpha-dystroglycan, and ISPD synthesizes CDP-ribitol, a donor substrate
for fukutin and FKRP
explanation: >-
Establishes the enzymatic function of fukutin as a ribitol-phosphate
transferase in the alpha-DG glycosylation pathway.
- name: FKRP
gene_term:
preferred_term: FKRP
term:
id: hgnc:17997
label: FKRP
association: Causative
features: >
FKRP transfers the second ribitol-phosphate. The most common cause of
dystroglycanopathy in European populations. The L276I mutation is a frequent
allele associated with milder LGMD2I (type C) phenotype.
evidence:
- reference: DOI:10.3233/jnd-230205
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Missense point mutations in the Fukutin-related protein (FKRP) gene cause
variable reduction in the synthesis of matriglycan on alpha-dystroglycan
(α-DG) and a wide range of disease severity
explanation: >-
FKRP mutations cause variable matriglycan reduction and a wide severity
spectrum.
- name: LARGE1
gene_term:
preferred_term: LARGE1
term:
id: hgnc:6511
label: LARGE1
association: Causative
features: >
LARGE1 is the bifunctional glycosyltransferase that polymerizes the terminal
matriglycan repeat on alpha-DG.
evidence:
- reference: DOI:10.7554/eLife.82811
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
is uniquely synthesized on α-dystroglycan (α-DG) by
like-acetylglucosaminyltransferase-1 (LARGE1)
explanation: >-
Identifies LARGE1 as the enzyme that synthesizes matriglycan on alpha-DG.
- reference: CGGV:assertion_98beb148-70ee-4448-8d53-12c26fddf855-2024-07-02T160000.000Z
reference_title: "LARGE1 / muscular dystrophy-dystroglycanopathy (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "LARGE1 | HGNC:6511 | muscular dystrophy-dystroglycanopathy | MONDO:0018276 | AR | Definitive"
explanation: ClinGen classifies the LARGE1-muscular dystrophy-dystroglycanopathy gene-disease relationship as definitive with autosomal recessive inheritance.
- name: CRPPA
gene_term:
preferred_term: CRPPA
term:
id: hgnc:37276
label: CRPPA
association: Causative
features: >
CRPPA (formerly ISPD) synthesizes CDP-ribitol, the donor substrate for
fukutin and FKRP.
evidence:
- reference: PMID:29081423
reference_title: "Muscular Dystrophy with Ribitol-Phosphate Deficiency: A Novel Post-Translational Mechanism in Dystroglycanopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
ISPD synthesizes CDP-ribitol, a donor substrate for fukutin and FKRP
explanation: >-
Identifies CRPPA/ISPD as the CDP-ribitol synthase.
- name: POMGNT2
gene_term:
preferred_term: POMGNT2
term:
id: hgnc:25902
label: POMGNT2
association: Causative
- name: POMK
gene_term:
preferred_term: POMK
term:
id: hgnc:26267
label: POMK
association: Causative
features: >
POMK phosphorylates the O-mannose on the core M3 glycan, required
for LARGE1 to extend matriglycan to full length.
evidence:
- reference: DOI:10.7554/eLife.82811
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
-mannose kinase (POMK) is required for LARGE1 to generate full-length
matriglycan on α-DG (~150–250 kDa)
explanation: >-
Demonstrates that POMK-mediated phosphorylation is a prerequisite for
full matriglycan extension by LARGE1.
- name: B3GALNT2
gene_term:
preferred_term: B3GALNT2
term:
id: hgnc:28596
label: B3GALNT2
association: Causative
- name: B4GAT1
gene_term:
preferred_term: B4GAT1
term:
id: hgnc:15685
label: B4GAT1
association: Causative
- name: RXYLT1
gene_term:
preferred_term: RXYLT1
term:
id: hgnc:13530
label: RXYLT1
association: Causative
- name: GMPPB
gene_term:
preferred_term: GMPPB
term:
id: hgnc:22932
label: GMPPB
association: Causative
features: >
GMPPB synthesizes GDP-mannose, the sugar donor for POMT1/POMT2.
- name: DAG1
gene_term:
preferred_term: DAG1
term:
id: hgnc:2666
label: DAG1
association: Causative
features: >
DAG1 encodes dystroglycan itself. Rare mutations in the mucin-like domain
disrupt glycosylation sites, causing primary dystroglycanopathy.
- name: DPM1
gene_term:
preferred_term: DPM1
term:
id: hgnc:3005
label: DPM1
association: Causative
- name: DPM2
gene_term:
preferred_term: DPM2
term:
id: hgnc:3006
label: DPM2
association: Causative
- name: DPM3
gene_term:
preferred_term: DPM3
term:
id: hgnc:3007
label: DPM3
association: Causative
treatments:
- name: Supportive care and rehabilitation
description: >
Multidisciplinary supportive care including physical therapy, respiratory
support, nutritional management, and orthopedic interventions to maintain
function and quality of life.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
- name: Physical therapy
description: >
Rehabilitation exercises to maintain mobility, prevent contractures, and
optimize remaining muscle function in milder phenotypes.
treatment_term:
preferred_term: physical therapy
term:
id: MAXO:0000011
label: physical therapy
- name: Genetic counseling
description: >
Genetic counseling for families to discuss recurrence risk (25% for autosomal
recessive), carrier testing, and prenatal diagnosis options.
treatment_term:
preferred_term: genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
- name: Ribitol supplementation
description: >
Oral ribitol supplementation is an emerging substrate enhancement therapy
specifically for FKRP-related dystroglycanopathy. Ribitol increases the
CDP-ribitol substrate pool, enhancing residual FKRP function and improving
matriglycan expression on alpha-DG.
treatment_term:
preferred_term: ribitol supplementation
term:
id: NCIT:C15986
label: Pharmacotherapy
notes: >
Ribitol therapy is specific to FKRP-related dystroglycanopathy (LGMD2I/LGMDR9).
Phase II (NCT04800874) and Phase III (NCT05775848) trials have shown biomarker improvements.
- name: AAV gene therapy
description: >
Adeno-associated virus (AAV)-mediated gene replacement therapy is in preclinical
development for FKRP-related dystroglycanopathy. AAV9-FKRP delivers functional
FKRP to skeletal and cardiac muscle.
treatment_term:
preferred_term: gene therapy
term:
id: MAXO:0001001
label: gene therapy
notes: >-
Preclinical studies show that combination of AAV-FKRP with ribitol is more
effective than either alone.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on the pathophysiology of Dystroglycanopathy. Focus on the molecular and cellular mechanisms underlying disease progression.
Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs
Target disease: Dystroglycanopathy (a spectrum of disorders caused by functional defects of dystroglycan—most commonly impaired glycosylation of α-dystroglycan). (cubilla2023dystroglycanopathiesgeneticbases pages 4-5, cubilla2023dystroglycanopathiesgeneticbases pages 3-4)
MONDO ID: Not directly present in the retrieved full-text sources. The Open Targets evidence snapshot used in this run indicates MONDO_0018276 (“muscular dystrophy-dystroglycanopathy”) and MONDO_0018282 (“neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan”), but those identifiers were returned as database output rather than as citable literature context in this report. Therefore, MONDO IDs should be confirmed via MONDO/Orphanet ontology lookup for production use. (benarroch2024the2024version pages 8-9, cubilla2023dystroglycanopathiesgeneticbases pages 4-5)
Dystroglycanopathies are muscular dystrophies caused by abnormal O-glycosylation of α-dystroglycan (α-DG), a core component of the dystrophin glycoprotein complex (DGC) that connects the extracellular matrix (ECM) to the intracellular actin cytoskeleton. (cubilla2023dystroglycanopathiesgeneticbases pages 3-4, cubilla2023dystroglycanopathiesgeneticbases pages 4-5)
A common nosologic division is: - Primary dystroglycanopathy: pathogenic variants in DAG1 (dystroglycan itself). (cubilla2023dystroglycanopathiesgeneticbases pages 4-5) - Secondary dystroglycanopathy: variants in the ≈20+ genes needed for α-DG functional glycosylation (O-mannosylation, nucleotide-sugar synthesis, glycan extension, and in some cases Golgi trafficking). (cubilla2023dystroglycanopathiesgeneticbases pages 4-5, cubilla2023dystroglycanopathiesgeneticbases pages 3-4)
The dystroglycanopathy spectrum spans severe congenital multisystem disease to later-onset limb-girdle muscular dystrophy phenotypes: - Walker–Warburg syndrome (WWS) is described as among the most severe forms, often detectable prenatally, featuring congenital muscular dystrophy plus major brain and eye anomalies. (cubilla2023dystroglycanopathiesgeneticbases pages 8-9) - Muscle-eye-brain (MEB) / Fukuyama congenital muscular dystrophy (FCMD) are classic congenital α-dystroglycanopathy syndromes with prominent CNS/ocular involvement. (cubilla2023dystroglycanopathiesgeneticbases pages 7-8) - Limb-girdle muscular dystrophy forms such as LGMD2I/R9 (FKRP-related) represent milder ends of the same mechanistic axis. (cubilla2023dystroglycanopathiesgeneticbases pages 8-9, unnikrishnan2023phenotypegenotypecharacterization pages 1-3)
In dystroglycanopathies, mutations reduce or abolish assembly of a specialized O-mannose–derived glycan culminating in matriglycan, a repeating disaccharide polymer on α-DG ([-3Xyl-α1,3-GlcA-β1-]n). This “functional glycan” is the key determinant of α-DG binding to ECM laminin-G (LG) domain proteins. (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, koff2023proteinomannosylationone pages 2-4)
Matriglycan mediates α-DG interactions with ECM ligands such as laminin, agrin, perlecan, and pikachurin, enabling mechanical stability and signaling functions across tissues (skeletal muscle, brain, eye, heart). (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, lu2024breakdownof pages 1-2)
Recent reviews synthesize the pathway as: 1) ER initiation by POMT1/POMT2 (O-mannosylation). (koff2023proteinomannosylationone pages 2-4, koff2023proteinomannosylationone pages 5-6) 2) Core M3 elaboration (e.g., POMGNT2, B3GALNT2). (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, koff2023proteinomannosylationone pages 2-4) 3) Phosphorylation by POMK, generating the phosphorylated “nucleus” needed for downstream steps. (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, koff2023proteinomannosylationone pages 5-6) 4) Ribitol-phosphate pathway: ISPD/CRPPA generates CDP-ribitol; FKTN and FKRP transfer ribitol-5-phosphate, enabling later LARGE1-dependent extension. (lu2024breakdownof pages 1-2, lu2024breakdownof pages 9-10) 5) Primer/linker assembly (e.g., TMEM5/RXYLT1 and B4GAT1) and finally 6) Polymerization by LARGE1, which extends matriglycan. (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, koff2023proteinomannosylationone pages 2-4)
Mechanistic consequence: reduction of matriglycan decreases α-DG ligand binding, disrupting the DGC-mediated ECM–cytoskeleton linkage and causing contraction-induced injury and downstream inflammation/fibrosis/regeneration cycles in muscle. (lu2024breakdownof pages 1-2, unnikrishnan2023phenotypegenotypecharacterization pages 1-3)
Loss of functional α-DG glycosylation weakens the sarcolemma–basal lamina connection, contributing to muscle fiber fragility and dystrophic degeneration. FKRP encodes a ribitol-5-phosphate transferase required for functional laminin-binding glycosylation on the sarcolemma. (lu2024breakdownof pages 1-2, unnikrishnan2023phenotypegenotypecharacterization pages 1-3)
Defective O-mannosylation (e.g., POMT loss) abolishes α-DG–ECM interactions required for pial basement membrane integrity, contributing to brain malformations and migration defects (cobblestone lissencephaly spectrum). (koff2023proteinomannosylationone pages 5-6, NCT00313677 chunk 2)
A 2024 eLife study provides strong mechanistic evidence that severe dystroglycan glycosylation loss in forebrain disrupts development and function of CCK+/CB1R+ inhibitory basket synapses onto hippocampal pyramidal neurons and reduces seizure threshold. (jahncke2024inhibitorycck+basket pages 1-2, jahncke2024inhibitorycck+basket pages 15-16)
Quantitatively, seizure susceptibility (flurothyl) tracks with glycosylation severity: generalized tonic-clonic seizure latency reductions were ~40.9% (Emx1Cre:Dag1 cKO), ~42.9% (Emx1Cre:Pomt2 cKO), and ~33.6% (Dag1cyto/-), while milder hypoglycosylation models showed smaller or no effects. (jahncke2024inhibitorycck+basket pages 13-15)
A 2024 Human Molecular Genetics zebrafish POMT1 loss model shows that loss of α-DG glycosylation causes retinal synapse defects (outer plexiform layer abnormalities, photoreceptor pedicle retraction) and axon guidance defects; importantly, these phenotypes depend on maternal pomt1 mRNA contribution, which can transiently sustain glycosylation early in development. (karas2024removalofpomt1 pages 6-7, karas2024removalofpomt1 pages 1-1)
| Module/Step | Gene (HGNC) | Protein/Function | Mechanistic Consequence | Key Citations |
|---|---|---|---|---|
| Dystroglycan Core | DAG1 | Core glycoprotein substrate ($\alpha$/$\beta$ subunits) | Primary dystroglycanopathy; loss of ECM linkage scaffold | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, cubilla2023dystroglycanopathiesgeneticbases pages 4-5, cubilla2023dystroglycanopathiesgeneticbases pages 23-24) |
| Sugar Metabolism | GMPPB | GDP-mannose pyrophosphorylase B; GDP-Man synthesis | Reduces GDP-mannose pool; limits substrate for O-mannosylation | (wang2024geneticallyengineeredmouse pages 37-41) |
| ER O-Mannosylation | POMT1 / POMT2 | Protein O-mannosyltransferases; initiate O-mannosylation | Abolishes initial O-mannose attachment; severe WWS/CMD phenotype | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, koff2023proteinomannosylationone pages 2-4, karas2024removalofpomt1 pages 1-1, koff2023proteinomannosylationone pages 5-6) |
| Core M3 Elaboration | POMGNT2 (GTDC2) | GlcNAc transferase; forms Core M3 (GlcNAc-$\beta$1,4-Man) | Prevents formation of Core M3; blocks functional glycosylation | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, koff2023proteinomannosylationone pages 2-4, lu2024breakdownof pages 1-2) |
| Core M3 Elaboration | B3GALNT2 | GalNAc transferase; extends Core M3 | Defective Core M3 structure; prevents phosphorylation | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, koff2023proteinomannosylationone pages 2-4, ma2024deepmutationalscanning pages 30-32) |
| Phosphorylation | POMK (SGK196) | Kinase; phosphorylates Mannose-C6 on Core M3 | Lack of phospho-mannose "nucleus" for ribitol addition | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, koff2023proteinomannosylationone pages 5-6, ma2024saturationmutagenesisreinforcedfunctional pages 26-27) |
| CDP-Ribitol Synthesis | ISPD (CRPPA) | CDP-L-ribitol pyrophosphorylase; synthesizes CDP-Rbo | Depletes sugar donor for FKTN/FKRP; severe hypoglycosylation | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, lu2024breakdownof pages 1-2, cubilla2023dystroglycanopathiesgeneticbases pages 22-23) |
| Ribitol Transfer | FKTN | Fukutin; first Ribitol-5-phosphate transferase | Fails to add first ribitol-P; blocks matriglycan initiation | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, lu2024breakdownof pages 1-2, ma2024saturationmutagenesisreinforcedfunctional pages 26-27, lu2024breakdownof pages 9-10) |
| Ribitol Transfer | FKRP | Fukutin-related protein; second Ribitol-5-P transferase | Fails to add second ribitol-P; LGMD2I to WWS spectrum | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, lu2024breakdownof pages 1-2, lu2024breakdownof pages 9-10) |
| Linker/Primer | RXYLT1 (TMEM5) | Ribitol-xylosyltransferase; adds Xylose to RboP | Disrupts glycan primer required for LARGE1 recognition | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, lu2024breakdownof pages 1-2, ma2024saturationmutagenesisreinforcedfunctional pages 26-27) |
| Linker/Primer | B4GAT1 | Glucuronyltransferase; adds GlcA to Xylose | Incomplete primer prevents LARGE1 binding/elongation | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, koff2023proteinomannosylationone pages 5-6, ma2024saturationmutagenesisreinforcedfunctional pages 26-27) |
| Matriglycan Polymerization | LARGE1 | Bifunctional glycosyltransferase (Xyl/GlcA) | Loss of laminin-binding matriglycan polymer; MDC1D | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, ma2024deepmutationalscanning pages 30-32, ma2024saturationmutagenesisreinforcedfunctional pages 26-27) |
| Adaptor Function | POMGNT1 | Glycosyltransferase (M1) & FKTN recruiter (M3) | M3 defect due to failure to recruit FKTN; MEB disease | (koff2023proteinomannosylationone pages 2-4, koff2023proteinomannosylationone pages 5-6) |
Table: This table summarizes the core molecular machinery involved in the O-mannosylation pathway and matriglycan synthesis, mapping specific genes to their enzymatic functions and the mechanistic consequences of their disruption.
| Category | Term Label (ID) | Evidence/Justification | Key Citations |
|---|---|---|---|
| GO: Bio Process | protein O-linked mannosylation (GO:0035269) | Core defect; failure to add O-mannose or extend matriglycan on $\alpha$-DG. | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, koff2023proteinomannosylationone pages 2-4) |
| GO: Bio Process | cell-matrix adhesion (GO:0007160) | Matriglycan mediates binding to laminin/agrin; loss disrupts ECM linkage. | (koff2023proteinomannosylationone pages 2-4, lu2024breakdownof pages 1-2) |
| GO: Bio Process | skeletal muscle regeneration (GO:0043403) | Impaired satellite cell differentiation (GMPPB model); revertant fibers. | (wang2024geneticallyengineeredmouse pages 37-41, lu2024breakdownof pages 4-6) |
| GO: Bio Process | axon guidance (GO:0007411) | Defective retinal/brain axon targeting in pomt1 zebrafish and mouse models. | (karas2024removalofpomt1 pages 1-1, karas2024removalofpomt1 pages 6-7) |
| GO: Bio Process | chemical synaptic transmission (GO:0007268) | Functional defects in inhibitory CCK+ basket synapses; increased excitability. | (jahncke2024inhibitorycck+basket pages 15-16, jahncke2024inhibitorycck+basket pages 13-15) |
| GO: Bio Process | Wnt signaling pathway (GO:0016055) | Downregulated in GMPPB-deficient muscle; activation rescues myogenesis. | (wang2024geneticallyengineeredmouse pages 37-41) |
| GO: Cell Comp | dystrophin-associated glycoprotein complex (GO:0016010) | $\alpha$-DG is the central extracellular receptor of this complex. | (lu2024breakdownof pages 1-2, koff2023proteinomannosylationone pages 5-6) |
| GO: Cell Comp | sarcolemma (GO:0042383) | Primary site of pathology; loss of integrity leads to CK leak. | (unnikrishnan2023phenotypegenotypecharacterization pages 1-3, wang2024geneticallyengineeredmouse pages 37-41) |
| GO: Cell Comp | neuromuscular junction (GO:0031594) | Structural defects; reduced $\alpha$-bungarotoxin staining in pomt1 mutants. | (wang2024geneticallyengineeredmouse pages 37-41, karas2024removalofpomt1 pages 10-11) |
| GO: Cell Comp | Golgi apparatus (GO:0005794) | Site of ribitol addition (FKRP) and matriglycan elongation (LARGE1). | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, lu2024breakdownof pages 9-10) |
| Cell Type (CL) | skeletal muscle satellite cell (CL:0000594) | Defective differentiation and regeneration in GMPPB and FKRP models. | (wang2024geneticallyengineeredmouse pages 37-41, lu2024breakdownof pages 4-6) |
| Cell Type (CL) | GABAergic interneuron (CL:0000617) | Specifically CCK+/CB1R+ basket cells show axon targeting/synapse defects. | (jahncke2024inhibitorycck+basket pages 15-16, jahncke2024inhibitorycck+basket pages 1-2) |
| Cell Type (CL) | photoreceptor cell (CL:0000210) | Synapse loss and degeneration in pomt1 zebrafish models. | (karas2024removalofpomt1 pages 3-4, karas2024removalofpomt1 pages 10-11) |
| Anatomy (UBERON) | hippocampus CA1 (UBERON:0003881) | Locus of inhibitory synapse defects and seizure genesis in models. | (jahncke2024inhibitorycck+basket pages 13-15, jahncke2024inhibitorycck+basket pages 10-11) |
| Anatomy (UBERON) | retina outer plexiform layer (UBERON:0005393) | Discontinuous synaptic staining and pedicle retraction in pomt1 mutants. | (karas2024removalofpomt1 pages 6-7, karas2024removalofpomt1 pages 10-11) |
| Phenotype (HP) | Muscular dystrophy (HP:0003560) | Progressive weakness, histology of degeneration/regeneration. | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, unnikrishnan2023phenotypegenotypecharacterization pages 1-3) |
| Phenotype (HP) | Seizures (HP:0001250) | Increased susceptibility/reduced latency in hypoglycosylated mice. | (jahncke2024inhibitorycck+basket pages 15-16, jahncke2024inhibitorycck+basket pages 13-15) |
| Phenotype (HP) | Global developmental delay (HP:0001263) | Common initial presentation in FKRP and severe CMD cohorts. | (unnikrishnan2023phenotypegenotypecharacterization pages 1-3) |
| Phenotype (HP) | Elevated serum creatine kinase (HP:0003236) | Marker of membrane leak; observed in GMPPB mice and human cohorts. | (wang2024geneticallyengineeredmouse pages 37-41, unnikrishnan2023phenotypegenotypecharacterization pages 1-3) |
| Phenotype (HP) | Cobblestone lissencephaly (HP:0007260) | Associated with migration defects and pial basement membrane rupture. | (koff2023proteinomannosylationone pages 5-6, NCT00313677 chunk 2) |
Table: This table maps key pathophysiological mechanisms, cellular locations, and clinical features of dystroglycanopathy to standardized ontology terms (GO, CL, UBERON, HP), supported by recent evidence.
Biallelic variants in DAG1 or α-DG glycosylation pathway genes reduce matriglycan synthesis, decreasing ECM ligand binding. (cubilla2023dystroglycanopathiesgeneticbases pages 4-5, cubilla2023dystroglycanopathiesgeneticbases pages 7-8)
FKRP cohort (India, 2023): among 9 unrelated patients with FKRP mutations, CK ranged 2,793–32,396 U/L (mean 12,120 U/L); 3 had lost ambulation by last follow-up (median age ~7 years, range 6.5–9), and 3 never achieved independent ambulation, showing clinically meaningful variability even within one gene. (unnikrishnan2023phenotypegenotypecharacterization pages 1-3)
Seizure susceptibility in severe murine forebrain dystroglycanopathy models aligns with selective inhibitory synapse defects; seizure latency reductions of ~33–43% are reported depending on genotype (see Section 2.3). (jahncke2024inhibitorycck+basket pages 13-15, jahncke2024inhibitorycck+basket pages 15-16)
Retinal synapse loss and photoreceptor structural defects are demonstrated after POMT1 loss in zebrafish, consistent with the role of matriglycan-dependent α-DG interactions in eye development and synapse maintenance. (karas2024removalofpomt1 pages 6-7, karas2024removalofpomt1 pages 10-11)
| Year | Citation | Title (Short) | Type | Key Contribution | PMID | URL | Supporting Citations |
|---|---|---|---|---|---|---|---|
| 2024 | Lam et al. | Dual FKRP/FST gene therapy... | Primary Study | Dual AAV-FKRP/Follistatin therapy restores $\alpha$-DG glycosylation and increases muscle mass in LGMDR9 mice. | - | 10.1016/j.ymthe.2024.06.028 | (lam2024dualfkrpfstgene pages 1-2, lam2024dualfkrpfstgene pages 7-8, lam2024dualfkrpfstgene media f92354a7) |
| 2024 | Karas et al. | Removal of pomt1 in zebrafish... | Primary Study | Validated pomt1 null zebrafish; showed maternal mRNA delays brain/eye/muscle phenotypes until >5 dpf. | - | 10.1093/hmg/ddae006 | (karas2024removalofpomt1 pages 1-1, karas2024removalofpomt1 pages 6-7, karas2024removalofpomt1 pages 1-2) |
| 2024 | Jahncke et al. | Inhibitory CCK+ basket synapse... | Primary Study | Glycosylation defects specifically disrupt CCK+/CB1R+ inhibitory synapses, increasing seizure susceptibility. | - | 10.7554/elife.87965 | (jahncke2024inhibitorycck+basket pages 15-16, jahncke2024inhibitorycck+basket pages 1-2, jahncke2024inhibitorycck+basket pages 10-11) |
| 2024 | Rajasingham et al. | Validation of a novel western blot... | Method Validation | Validated quantitative multiplex fluorescent Western blot for $\alpha$-DG glycosylation (IIH6/Core) in muscle biopsies. | - | 10.1007/s10974-024-09670-y | (rajasingham2024validationofa pages 2-4, rajasingham2024validationofa pages 1-2, rajasingham2024validationofa pages 8-10) |
| 2024 | Lu et al. | Break Down of the Complexity... | Review | Addresses FKRP genotype-phenotype disconnect; highlights regeneration-associated matriglycan variability in biopsies. | - | 10.3233/jnd-230205 | (lu2024breakdownof pages 1-2, lu2024breakdownof pages 4-6) |
| 2024 | Wang et al. | Genetically Engineered Mouse Models... | Primary (Preprint) | GMPPB loss depletes GDP-mannose, impairs satellite cell differentiation via Wnt, rescued by AAV-GMPPB. | - | 10.21203/rs.3.rs-4502560/v1 | (wang2024geneticallyengineeredmouse pages 37-41) |
| 2023 | Cubilla et al. | Dystroglycanopathies: Genetic Bases... | Review | Comprehensive classification of primary vs secondary dystroglycanopathies and O-mannosylation genes. | - | 10.1590/2326-4594-jiems-2022-0005 | (cubilla2023dystroglycanopathiesgeneticbases pages 7-8, cubilla2023dystroglycanopathiesgeneticbases pages 4-5, cubilla2023dystroglycanopathiesgeneticbases pages 3-4) |
| 2023 | ML Bio Solutions | Study to Evaluate... BBP-418 | Clinical Trial (Ph3) | Phase 3 trial (NCT05775848) testing oral Ribitol (BBP-418) efficacy in LGMD2I/R9; primary endpoint NSAD. | - | NCT05775848 | (NCT05775848 chunk 1) |
Table: This table summarizes significant primary studies, reviews, and clinical trials from 2023 and 2024 that have advanced the understanding of dystroglycanopathy pathophysiology, diagnosis, and treatment.
Key themes from 2023–2024 literature: 1) Circuit-level neurobiology: severe dystroglycan glycosylation loss causes selective inhibitory synapse defects (CCK+/CB1R+) and seizure vulnerability, separating synapse-organizing roles from gross migration defects in some contexts. (jahncke2024inhibitorycck+basket pages 15-16, jahncke2024inhibitorycck+basket pages 17-18) 2) Developmental timing: maternal mRNA/protein contribution can mask early phenotypes in zebrafish; true maternal-zygotic knockouts reveal early retinal/axon guidance and NMJ deficits. (karas2024removalofpomt1 pages 6-7, karas2024removalofpomt1 pages 1-1) 3) Biomarker modernization: validated quantitative multiplex fluorescence western blot provides a practical method to measure glycosylated vs core α-DG in small biopsies, supporting trials/longitudinal monitoring. (rajasingham2024validationofa pages 1-2, rajasingham2024validationofa pages 12-13) 4) Mechanisms beyond ECM linkage: GMPPB deficiency links glycosylation defects to altered intracellular programs (Ca2+ handling, Wnt/β-catenin signaling) and impaired myogenic differentiation, highlighting modifiers and downstream targets. (wang2024geneticallyengineeredmouse pages 37-41)
A 2024 validated assay quantifies glycosylated and core α-DG from tibialis anterior biopsies using dual-channel fluorescence western blot with IIH6C4 (functional matriglycan epitope) and a core α-DG antibody, with calibration curves and an estimated LLOQ of ~1 µg total protein (estimated detection ~13 pg α-DG). (rajasingham2024validationofa pages 2-4, rajasingham2024validationofa pages 12-13)
Ribitol (BBP-418) - Phase 3, randomized placebo-controlled trial in LGMD2I/R9: NCT05775848 (start 2023-05-31), Phase 3, 81 planned participants, primary endpoint: change from baseline in North Star Assessment for Limb Girdle Muscular Dystrophy at 36 months; key secondary outcomes include 10m walk velocity and FVC%. (NCT05775848 chunk 1) - Phase 2 open-label trial: NCT04800874 (start 2021-02-18), 14 participants; includes PK/PD and biopsy-based assessments (including N-terminal α-DG measures and tibialis anterior biopsy). (NCT04800874 chunk 1)
FKRP gene therapy (AAV9-based; examples) - ATA-100 (GNT0006): NCT05224505, Phase 1, open dose-escalation, 6 participants, start 2022-09-01, endpoints include safety plus functional tests, MRI, and biopsy glycosylation measures. (NCT05224505 chunk 1) - AB-1003 (LION-101): NCT05230459, recruiting; includes Phase 1 dose escalation and adaptive Phase 2, start 2023-05-15, estimated 10 participants, primary endpoint safety over 52 weeks. (NCT05230459 chunk 1)
A 2024 Molecular Therapy study demonstrates a dual-gene AAV approach (FKRP + follistatin) in FKRP P448L mice: - Restores IIH6-detected α-DG glycosylation with band shift toward ~156 kDa and increased IIH6-positive fibers in diaphragm/heart with dual therapy versus FKRP alone (with reported significance for diaphragm). (lam2024dualfkrpfstgene pages 7-8, lam2024dualfkrpfstgene media f92354a7) - Quantitatively, at 6 months the high-dose dual vector increased muscle FKRP protein from ~9.7±1.4-fold (FKRP alone) to 109±59-fold (dual), and increased serum human follistatin to 39.7±8.0 ng/mL (dual) versus ~6.4±2.2 ng/mL (FST alone). (lam2024dualfkrpfstgene pages 7-8)
A 2024 review argues that many FKRP missense variants retain partial function, and matriglycan expression may be preserved or re-expressed during later development and especially during regeneration, creating mosaic patterns and sampling bias in biopsies; this can produce weak or inconsistent correlations between matriglycan levels and clinical severity. (lu2024breakdownof pages 1-2, lu2024breakdownof pages 2-4)
The same review recommends fiber-level quantification (e.g., ImageJ Multi Point membrane intensity measures, exclusion/stratification of regenerating fibers, ≥100 fibers) alongside complementary bulk approaches (western blot) to improve interpretability for trials. (lu2024breakdownof pages 6-8, lu2024breakdownof pages 8-9)
The 2024 eLife study supports a “glycosylation threshold” concept where severe hypoglycosylation (forebrain Dag1 or Pomt2 loss) yields functional inhibitory synapse defects and seizure vulnerability, whereas partial hypoglycosylation can preserve synaptic function. (jahncke2024inhibitorycck+basket pages 15-16, jahncke2024inhibitorycck+basket pages 13-15)
Most 2023–2024 sources retrieved here did not include PMIDs in the extracted text, and this RAG run did not retrieve PubMed metadata fields for them. One indirect PMID signal exists via Open Targets evidence (e.g., POMT1 association including PMID 38272461), but those outputs are not part of the citable paper text context for this report. Therefore, PMIDs should be added by external PubMed lookup using the DOIs/URLs provided in this report. (benarroch2024the2024version pages 8-9)
A 2024 FKRP review emphasizes the interpretability issue of biopsy matriglycan: biopsies can show “fibers of very weak matriglycan and clusters of RFs with strong matriglycan expression,” highlighting mosaicism and the need for robust quantification. (lu2024breakdownof pages 8-9)
References
(cubilla2023dystroglycanopathiesgeneticbases pages 4-5): M.A. Cubilla, G.M. Papazoglu, and C.G. Asteggiano. Dystroglycanopathies: genetic bases of muscular dystrophies due to alteration in the o-glycosylation of α-dystroglycan. Journal of Inborn Errors of Metabolism and Screening, Apr 2023. URL: https://doi.org/10.1590/2326-4594-jiems-2022-0005, doi:10.1590/2326-4594-jiems-2022-0005. This article has 3 citations.
(cubilla2023dystroglycanopathiesgeneticbases pages 3-4): M.A. Cubilla, G.M. Papazoglu, and C.G. Asteggiano. Dystroglycanopathies: genetic bases of muscular dystrophies due to alteration in the o-glycosylation of α-dystroglycan. Journal of Inborn Errors of Metabolism and Screening, Apr 2023. URL: https://doi.org/10.1590/2326-4594-jiems-2022-0005, doi:10.1590/2326-4594-jiems-2022-0005. This article has 3 citations.
(benarroch2024the2024version pages 8-9): Louise Benarroch, Gisèle Bonne, François Rivier, and Dalil Hamroun. The 2024 version of the gene table of neuromuscular disorders (nuclear genome). Neuromuscular Disorders, 34:126-170, Jan 2024. URL: https://doi.org/10.1016/j.nmd.2023.12.007, doi:10.1016/j.nmd.2023.12.007. This article has 32 citations and is from a peer-reviewed journal.
(cubilla2023dystroglycanopathiesgeneticbases pages 8-9): M.A. Cubilla, G.M. Papazoglu, and C.G. Asteggiano. Dystroglycanopathies: genetic bases of muscular dystrophies due to alteration in the o-glycosylation of α-dystroglycan. Journal of Inborn Errors of Metabolism and Screening, Apr 2023. URL: https://doi.org/10.1590/2326-4594-jiems-2022-0005, doi:10.1590/2326-4594-jiems-2022-0005. This article has 3 citations.
(cubilla2023dystroglycanopathiesgeneticbases pages 7-8): M.A. Cubilla, G.M. Papazoglu, and C.G. Asteggiano. Dystroglycanopathies: genetic bases of muscular dystrophies due to alteration in the o-glycosylation of α-dystroglycan. Journal of Inborn Errors of Metabolism and Screening, Apr 2023. URL: https://doi.org/10.1590/2326-4594-jiems-2022-0005, doi:10.1590/2326-4594-jiems-2022-0005. This article has 3 citations.
(unnikrishnan2023phenotypegenotypecharacterization pages 1-3): Gopikrishnan Unnikrishnan, Kiran Polavarapu, Mainak Bardhan, Saraswati Nashi, Seena Vengalil, Veeramani Preethish-Kumar, Ravi Kiran Valasani, Akshata Huddar, Vikas Nishadham, Bevinahalli Nanjegowda Nandeesh, and Atchayaram Nalini. Phenotype genotype characterization of fkrp-related muscular dystrophy among indian patients. Journal of Neuromuscular Diseases, 10:615-626, May 2023. URL: https://doi.org/10.3233/jnd-221618, doi:10.3233/jnd-221618. This article has 7 citations and is from a peer-reviewed journal.
(koff2023proteinomannosylationone pages 2-4): Melissa Koff, Pedro Monagas-Valentin, Boris Novikov, Ishita Chandel, and Vladislav Panin. Protein o-mannosylation: one sugar, several pathways, many functions. Glycobiology, 33:911-926, Aug 2023. URL: https://doi.org/10.1093/glycob/cwad067, doi:10.1093/glycob/cwad067. This article has 17 citations and is from a peer-reviewed journal.
(lu2024breakdownof pages 1-2): Qi L. Lu, Molly C. Holbrook, Marcela P. Cataldi, and Anthony Blaeser. Break down of the complexity and inconsistency between levels of matriglycan and disease phenotype in fkrp-related dystroglycanopathies: a review and model of interpretation. Journal of Neuromuscular Diseases, 11:275-284, Jan 2024. URL: https://doi.org/10.3233/jnd-230205, doi:10.3233/jnd-230205. This article has 2 citations and is from a peer-reviewed journal.
(koff2023proteinomannosylationone pages 5-6): Melissa Koff, Pedro Monagas-Valentin, Boris Novikov, Ishita Chandel, and Vladislav Panin. Protein o-mannosylation: one sugar, several pathways, many functions. Glycobiology, 33:911-926, Aug 2023. URL: https://doi.org/10.1093/glycob/cwad067, doi:10.1093/glycob/cwad067. This article has 17 citations and is from a peer-reviewed journal.
(lu2024breakdownof pages 9-10): Qi L. Lu, Molly C. Holbrook, Marcela P. Cataldi, and Anthony Blaeser. Break down of the complexity and inconsistency between levels of matriglycan and disease phenotype in fkrp-related dystroglycanopathies: a review and model of interpretation. Journal of Neuromuscular Diseases, 11:275-284, Jan 2024. URL: https://doi.org/10.3233/jnd-230205, doi:10.3233/jnd-230205. This article has 2 citations and is from a peer-reviewed journal.
(NCT00313677 chunk 2): Katherine Mathews. Clinical Trial Readiness for the Dystroglycanopathies. Katherine Mathews. 2006. ClinicalTrials.gov Identifier: NCT00313677
(jahncke2024inhibitorycck+basket pages 1-2): Jennifer N Jahncke, Daniel S Miller, Milana Krush, Eric Schnell, and Kevin M Wright. Inhibitory cck+ basket synapse defects in mouse models of dystroglycanopathy. eLife, Jan 2024. URL: https://doi.org/10.7554/elife.87965, doi:10.7554/elife.87965. This article has 8 citations and is from a domain leading peer-reviewed journal.
(jahncke2024inhibitorycck+basket pages 15-16): Jennifer N Jahncke, Daniel S Miller, Milana Krush, Eric Schnell, and Kevin M Wright. Inhibitory cck+ basket synapse defects in mouse models of dystroglycanopathy. eLife, Jan 2024. URL: https://doi.org/10.7554/elife.87965, doi:10.7554/elife.87965. This article has 8 citations and is from a domain leading peer-reviewed journal.
(jahncke2024inhibitorycck+basket pages 13-15): Jennifer N Jahncke, Daniel S Miller, Milana Krush, Eric Schnell, and Kevin M Wright. Inhibitory cck+ basket synapse defects in mouse models of dystroglycanopathy. eLife, Jan 2024. URL: https://doi.org/10.7554/elife.87965, doi:10.7554/elife.87965. This article has 8 citations and is from a domain leading peer-reviewed journal.
(karas2024removalofpomt1 pages 6-7): Brittany F Karas, Kristin R Terez, Shorbon Mowla, Namarata Battula, Kyle P Flannery, Brian M Gural, Grace Aboussleman, Numa Mubin, and M Chiara Manzini. Removal of pomt1 in zebrafish leads to loss of α-dystroglycan glycosylation and dystroglycanopathy phenotypes. Human Molecular Genetics, 33:709-723, Jan 2024. URL: https://doi.org/10.1093/hmg/ddae006, doi:10.1093/hmg/ddae006. This article has 8 citations and is from a domain leading peer-reviewed journal.
(karas2024removalofpomt1 pages 1-1): Brittany F Karas, Kristin R Terez, Shorbon Mowla, Namarata Battula, Kyle P Flannery, Brian M Gural, Grace Aboussleman, Numa Mubin, and M Chiara Manzini. Removal of pomt1 in zebrafish leads to loss of α-dystroglycan glycosylation and dystroglycanopathy phenotypes. Human Molecular Genetics, 33:709-723, Jan 2024. URL: https://doi.org/10.1093/hmg/ddae006, doi:10.1093/hmg/ddae006. This article has 8 citations and is from a domain leading peer-reviewed journal.
(cubilla2023dystroglycanopathiesgeneticbases pages 23-24): M.A. Cubilla, G.M. Papazoglu, and C.G. Asteggiano. Dystroglycanopathies: genetic bases of muscular dystrophies due to alteration in the o-glycosylation of α-dystroglycan. Journal of Inborn Errors of Metabolism and Screening, Apr 2023. URL: https://doi.org/10.1590/2326-4594-jiems-2022-0005, doi:10.1590/2326-4594-jiems-2022-0005. This article has 3 citations.
(wang2024geneticallyengineeredmouse pages 37-41): Yuxiang Wang, Ziwei fu, Wangtong Wang, Yanyan Chen, Chenyang Zhang, Ju Yang, Hua Yang, Bing Yan, Baoming Gong, Weiqiao Lu, Ying Liu, Lei Sun, Hao Jiang, Zhao Zhang, Bo Chen, and Xiuping Liu. Genetically engineered mouse models unveil mechanisms and therapeutic strategies for gmppb-associated dystroglycanopathy. Aug 2024. URL: https://doi.org/10.21203/rs.3.rs-4502560/v1, doi:10.21203/rs.3.rs-4502560/v1.
(ma2024deepmutationalscanning pages 30-32): Kaiyue Ma, Shushu Huang, Kenneth K. Ng, N. Lake, Soumya Joseph, Jenny Xu, A. Lek, Lin Ge, KG Woodman, K. Koczwara, Justin Cohen, Vincent Ho, Christine L. O’Connor, M. Brindley, Kevin P. Campbell, and M. Lek. Deep mutational scanning in disease-related genes with saturation mutagenesis-reinforced functional assays (smurf). Dataset, Aug 2024. URL: https://doi.org/10.17632/fgn9myv746.1, doi:10.17632/fgn9myv746.1. This article has 3 citations.
(ma2024saturationmutagenesisreinforcedfunctional pages 26-27): Kaiyue Ma, Shushu Huang, Kenneth K. Ng, Nicole J. Lake, Soumya Joseph, Jenny Xu, Angela Lek, Lin Ge, Keryn G. Woodman, Katherine E. Koczwara, Justin Cohen, Vincent Ho, Christine L. O’Connor, Melinda A. Brindley, Kevin P. Campbell, and Monkol Lek. Saturation mutagenesis-reinforced functional assays for disease-related genes. Cell, 187:6707-6724.e22, Nov 2024. URL: https://doi.org/10.1016/j.cell.2024.08.047, doi:10.1016/j.cell.2024.08.047. This article has 17 citations and is from a highest quality peer-reviewed journal.
(cubilla2023dystroglycanopathiesgeneticbases pages 22-23): M.A. Cubilla, G.M. Papazoglu, and C.G. Asteggiano. Dystroglycanopathies: genetic bases of muscular dystrophies due to alteration in the o-glycosylation of α-dystroglycan. Journal of Inborn Errors of Metabolism and Screening, Apr 2023. URL: https://doi.org/10.1590/2326-4594-jiems-2022-0005, doi:10.1590/2326-4594-jiems-2022-0005. This article has 3 citations.
(NCT04800874 chunk 1): Study of BBP-418 in Patients With LGMD2I. ML Bio Solutions, Inc.. 2021. ClinicalTrials.gov Identifier: NCT04800874
(NCT05775848 chunk 1): Study to Evaluate the Efficacy and Safety of BBP-418 (Ribitol) in Patients With Limb Girdle Muscular Dystrophy 2I (LGMD2I). ML Bio Solutions, Inc.. 2023. ClinicalTrials.gov Identifier: NCT05775848
(karas2024removalofpomt1 pages 10-11): Brittany F Karas, Kristin R Terez, Shorbon Mowla, Namarata Battula, Kyle P Flannery, Brian M Gural, Grace Aboussleman, Numa Mubin, and M Chiara Manzini. Removal of pomt1 in zebrafish leads to loss of α-dystroglycan glycosylation and dystroglycanopathy phenotypes. Human Molecular Genetics, 33:709-723, Jan 2024. URL: https://doi.org/10.1093/hmg/ddae006, doi:10.1093/hmg/ddae006. This article has 8 citations and is from a domain leading peer-reviewed journal.
(lu2024breakdownof pages 4-6): Qi L. Lu, Molly C. Holbrook, Marcela P. Cataldi, and Anthony Blaeser. Break down of the complexity and inconsistency between levels of matriglycan and disease phenotype in fkrp-related dystroglycanopathies: a review and model of interpretation. Journal of Neuromuscular Diseases, 11:275-284, Jan 2024. URL: https://doi.org/10.3233/jnd-230205, doi:10.3233/jnd-230205. This article has 2 citations and is from a peer-reviewed journal.
(karas2024removalofpomt1 pages 3-4): Brittany F Karas, Kristin R Terez, Shorbon Mowla, Namarata Battula, Kyle P Flannery, Brian M Gural, Grace Aboussleman, Numa Mubin, and M Chiara Manzini. Removal of pomt1 in zebrafish leads to loss of α-dystroglycan glycosylation and dystroglycanopathy phenotypes. Human Molecular Genetics, 33:709-723, Jan 2024. URL: https://doi.org/10.1093/hmg/ddae006, doi:10.1093/hmg/ddae006. This article has 8 citations and is from a domain leading peer-reviewed journal.
(jahncke2024inhibitorycck+basket pages 10-11): Jennifer N Jahncke, Daniel S Miller, Milana Krush, Eric Schnell, and Kevin M Wright. Inhibitory cck+ basket synapse defects in mouse models of dystroglycanopathy. eLife, Jan 2024. URL: https://doi.org/10.7554/elife.87965, doi:10.7554/elife.87965. This article has 8 citations and is from a domain leading peer-reviewed journal.
(lu2024breakdownof pages 2-4): Qi L. Lu, Molly C. Holbrook, Marcela P. Cataldi, and Anthony Blaeser. Break down of the complexity and inconsistency between levels of matriglycan and disease phenotype in fkrp-related dystroglycanopathies: a review and model of interpretation. Journal of Neuromuscular Diseases, 11:275-284, Jan 2024. URL: https://doi.org/10.3233/jnd-230205, doi:10.3233/jnd-230205. This article has 2 citations and is from a peer-reviewed journal.
(karas2024removalofpomt1 pages 7-8): Brittany F Karas, Kristin R Terez, Shorbon Mowla, Namarata Battula, Kyle P Flannery, Brian M Gural, Grace Aboussleman, Numa Mubin, and M Chiara Manzini. Removal of pomt1 in zebrafish leads to loss of α-dystroglycan glycosylation and dystroglycanopathy phenotypes. Human Molecular Genetics, 33:709-723, Jan 2024. URL: https://doi.org/10.1093/hmg/ddae006, doi:10.1093/hmg/ddae006. This article has 8 citations and is from a domain leading peer-reviewed journal.
(lam2024dualfkrpfstgene pages 1-2): Patricia Lam, Deborah A. Zygmunt, Anna Ashbrook, Macey Bennett, Tatyana A. Vetter, and Paul T. Martin. Dual fkrp/fst gene therapy normalizes ambulation, increases strength, decreases pathology, and amplifies gene expression in lgmdr9 mice. Molecular Therapy, 32:2604-2623, Aug 2024. URL: https://doi.org/10.1016/j.ymthe.2024.06.028, doi:10.1016/j.ymthe.2024.06.028. This article has 3 citations and is from a highest quality peer-reviewed journal.
(lam2024dualfkrpfstgene pages 7-8): Patricia Lam, Deborah A. Zygmunt, Anna Ashbrook, Macey Bennett, Tatyana A. Vetter, and Paul T. Martin. Dual fkrp/fst gene therapy normalizes ambulation, increases strength, decreases pathology, and amplifies gene expression in lgmdr9 mice. Molecular Therapy, 32:2604-2623, Aug 2024. URL: https://doi.org/10.1016/j.ymthe.2024.06.028, doi:10.1016/j.ymthe.2024.06.028. This article has 3 citations and is from a highest quality peer-reviewed journal.
(lam2024dualfkrpfstgene media f92354a7): Patricia Lam, Deborah A. Zygmunt, Anna Ashbrook, Macey Bennett, Tatyana A. Vetter, and Paul T. Martin. Dual fkrp/fst gene therapy normalizes ambulation, increases strength, decreases pathology, and amplifies gene expression in lgmdr9 mice. Molecular Therapy, 32:2604-2623, Aug 2024. URL: https://doi.org/10.1016/j.ymthe.2024.06.028, doi:10.1016/j.ymthe.2024.06.028. This article has 3 citations and is from a highest quality peer-reviewed journal.
(karas2024removalofpomt1 pages 1-2): Brittany F Karas, Kristin R Terez, Shorbon Mowla, Namarata Battula, Kyle P Flannery, Brian M Gural, Grace Aboussleman, Numa Mubin, and M Chiara Manzini. Removal of pomt1 in zebrafish leads to loss of α-dystroglycan glycosylation and dystroglycanopathy phenotypes. Human Molecular Genetics, 33:709-723, Jan 2024. URL: https://doi.org/10.1093/hmg/ddae006, doi:10.1093/hmg/ddae006. This article has 8 citations and is from a domain leading peer-reviewed journal.
(rajasingham2024validationofa pages 2-4): Thulashitha Rajasingham, Hector M. Rodriguez, Andreas Betz, Douglas M. Sproule, and Uma Sinha. Validation of a novel western blot assay to monitor patterns and levels of alpha dystroglycan in skeletal muscle of patients with limb girdle muscular dystrophies. Journal of Muscle Research and Cell Motility, 45:123-138, Apr 2024. URL: https://doi.org/10.1007/s10974-024-09670-y, doi:10.1007/s10974-024-09670-y. This article has 3 citations and is from a peer-reviewed journal.
(rajasingham2024validationofa pages 1-2): Thulashitha Rajasingham, Hector M. Rodriguez, Andreas Betz, Douglas M. Sproule, and Uma Sinha. Validation of a novel western blot assay to monitor patterns and levels of alpha dystroglycan in skeletal muscle of patients with limb girdle muscular dystrophies. Journal of Muscle Research and Cell Motility, 45:123-138, Apr 2024. URL: https://doi.org/10.1007/s10974-024-09670-y, doi:10.1007/s10974-024-09670-y. This article has 3 citations and is from a peer-reviewed journal.
(rajasingham2024validationofa pages 8-10): Thulashitha Rajasingham, Hector M. Rodriguez, Andreas Betz, Douglas M. Sproule, and Uma Sinha. Validation of a novel western blot assay to monitor patterns and levels of alpha dystroglycan in skeletal muscle of patients with limb girdle muscular dystrophies. Journal of Muscle Research and Cell Motility, 45:123-138, Apr 2024. URL: https://doi.org/10.1007/s10974-024-09670-y, doi:10.1007/s10974-024-09670-y. This article has 3 citations and is from a peer-reviewed journal.
(jahncke2024inhibitorycck+basket pages 17-18): Jennifer N Jahncke, Daniel S Miller, Milana Krush, Eric Schnell, and Kevin M Wright. Inhibitory cck+ basket synapse defects in mouse models of dystroglycanopathy. eLife, Jan 2024. URL: https://doi.org/10.7554/elife.87965, doi:10.7554/elife.87965. This article has 8 citations and is from a domain leading peer-reviewed journal.
(rajasingham2024validationofa pages 12-13): Thulashitha Rajasingham, Hector M. Rodriguez, Andreas Betz, Douglas M. Sproule, and Uma Sinha. Validation of a novel western blot assay to monitor patterns and levels of alpha dystroglycan in skeletal muscle of patients with limb girdle muscular dystrophies. Journal of Muscle Research and Cell Motility, 45:123-138, Apr 2024. URL: https://doi.org/10.1007/s10974-024-09670-y, doi:10.1007/s10974-024-09670-y. This article has 3 citations and is from a peer-reviewed journal.
(NCT05224505 chunk 1): ATA-100 (Formerly GNT0006) Gene Therapy Trial in Patients With LGMDR9. Atamyo Therapeutics. 2022. ClinicalTrials.gov Identifier: NCT05224505
(NCT05230459 chunk 1): A Study to Evaluate the Safety of AB-1003 (Previously LION-101) in Subjects With Genetic Confirmation of LGMD2I/R9 (Part1). AskBio Inc. 2023. ClinicalTrials.gov Identifier: NCT05230459
(lu2024breakdownof pages 6-8): Qi L. Lu, Molly C. Holbrook, Marcela P. Cataldi, and Anthony Blaeser. Break down of the complexity and inconsistency between levels of matriglycan and disease phenotype in fkrp-related dystroglycanopathies: a review and model of interpretation. Journal of Neuromuscular Diseases, 11:275-284, Jan 2024. URL: https://doi.org/10.3233/jnd-230205, doi:10.3233/jnd-230205. This article has 2 citations and is from a peer-reviewed journal.
(lu2024breakdownof pages 8-9): Qi L. Lu, Molly C. Holbrook, Marcela P. Cataldi, and Anthony Blaeser. Break down of the complexity and inconsistency between levels of matriglycan and disease phenotype in fkrp-related dystroglycanopathies: a review and model of interpretation. Journal of Neuromuscular Diseases, 11:275-284, Jan 2024. URL: https://doi.org/10.3233/jnd-230205, doi:10.3233/jnd-230205. This article has 2 citations and is from a peer-reviewed journal.
(lam2024dualfkrpfstgene media 72380d56): Patricia Lam, Deborah A. Zygmunt, Anna Ashbrook, Macey Bennett, Tatyana A. Vetter, and Paul T. Martin. Dual fkrp/fst gene therapy normalizes ambulation, increases strength, decreases pathology, and amplifies gene expression in lgmdr9 mice. Molecular Therapy, 32:2604-2623, Aug 2024. URL: https://doi.org/10.1016/j.ymthe.2024.06.028, doi:10.1016/j.ymthe.2024.06.028. This article has 3 citations and is from a highest quality peer-reviewed journal.