Limb-Girdle Muscular Dystrophy, Autosomal Dominant

1. Disease Information

Overview

Autosomal dominant limb-girdle muscular dystrophy (AD-LGMD) encompasses a heterogeneous group of genetic muscle disorders characterized by progressive weakness of the shoulder and hip girdle musculature, inherited in an autosomal dominant pattern. AD-LGMDs represent approximately 10–15% of all LGMDs, with the remainder being autosomal recessive forms (costa2022lgmdd2tnpo3related pages 1-2). The limb-girdle muscular dystrophies as a whole include more than 30 subtypes caused by mutations in multiple genes, leading to weakness and progressive muscle degeneration (sun2025recentinsightsinto pages 5-7).

Key Identifiers

• OMIM: LGMD1A (MIM 159000, MYOT); LGMD1B (MIM 159001, LMNA); LGMD1C (MIM 607801, CAV3); LGMD1E (MIM 615325, DES); TNPO3 gene OMIM 608423 (politano2024iscardiactransplantation pages 2-4, rodia2025novelinsightsinto pages 1-2)
• Orphanet: ORPHA:266 (Limb-girdle muscular dystrophy, general grouping)
• ICD-10: G71.0 (Muscular dystrophy)
• ICD-11: 8C70.0 (Limb-girdle muscular dystrophy)
• MONDO: MONDO:0015286 (autosomal dominant limb-girdle muscular dystrophy)

Synonyms and Alternative Names

Historical nomenclature includes LGMD1A through LGMD1I (Erb's limb-girdle dystrophy variants). The 2018 ENMC workshop established a revised classification: dominant forms are now designated LGMDD1 through LGMDD5 (jeong2023tripartitemotifcontainingprotein pages 10-11). Several classical LGMD1 designations were excluded from the refined classification because they were associated with other diseases, had limited family documentation, or were misreported (jeong2023tripartitemotifcontainingprotein pages 10-11).

Classification Summary

The following table summarizes all recognized and historically classified AD-LGMD subtypes:

Table: This table summarizes recognized autosomal dominant limb-girdle muscular dystrophy subtypes and historically named/excluded forms, with genes, loci, OMIM identifiers when available from retrieved evidence, onset, and hallmark clinical features. It is useful for mapping old and new nomenclature during knowledge-base curation.

2. Etiology

Disease Causal Factors

AD-LGMDs are exclusively genetic (Mendelian) disorders. Each subtype is caused by heterozygous pathogenic variants in a specific gene. The disease is inherited in an autosomal dominant pattern, meaning a single mutant allele is sufficient to cause disease (sun2025recentinsightsinto pages 5-7, bouchard2023limb–girdlemusculardystrophies pages 2-4).

Genetic Risk Factors (Causal Genes)

The currently recognized AD-LGMD subtypes and their causal genes are:

• LGMDD1 (formerly LGMD1D): DNAJB6 (7q36.3) — encodes a co-chaperone of the HSP70 system involved in Z-disc organization and protein quality control. Mutations are primarily clustered in the G/F region and J domain (sun2025recentinsightsinto pages 5-7, sarparanta2020neuromusculardiseasesdue pages 9-11).
• LGMDD2 (formerly LGMD1F): TNPO3 (7q32.1) — encodes transportin-3, a nuclear carrier for serine/arginine-rich (SR) proteins essential for mRNA splicing (rodia2025novelinsightsinto pages 1-2, costa2022lgmdd2tnpo3related pages 7-8).
• LGMDD3 (formerly LGMD1G): HNRNPDL (4p21) — encodes heterogeneous nuclear ribonucleoprotein D-like, involved in RNA binding and transcription regulation (sun2025recentinsightsinto pages 5-7, jeong2023tripartitemotifcontainingprotein pages 10-11).
• LGMDD4 (formerly LGMD1I): CAPN3 — encodes calpain-3, a cysteine protease involved in sarcomeric remodeling (sun2025recentinsightsinto pages 5-7, jeong2023tripartitemotifcontainingprotein pages 10-11).
• LGMDD5 (Bethlem myopathy): COL6A1, COL6A2, COL6A3 — encode collagen type VI subunits, components of the extracellular matrix (bouchard2023limb–girdlemusculardystrophies pages 5-6, jeong2023tripartitemotifcontainingprotein pages 10-11).

Historically classified but excluded from the revised LGMD classification are MYOT (LGMD1A), LMNA (LGMD1B), CAV3 (LGMD1C), DES (LGMD1E), and LGMD1H (gene unknown) (bouchard2023limb–girdlemusculardystrophies pages 2-4, politano2024iscardiactransplantation pages 2-4, jeong2023tripartitemotifcontainingprotein pages 10-11).

Environmental and Protective Factors

AD-LGMDs are monogenic disorders and are not significantly influenced by environmental risk factors. However, exercise interventions including aerobic and resistance training have demonstrated improvements in muscle strength and cardiorespiratory function across various LGMD subtypes (sun2025recentinsightsinto pages 18-21). No specific genetic protective factors or gene–environment interactions have been identified for AD-LGMD.

3. Phenotypes

Core Clinical Features

The hallmark phenotype shared across AD-LGMD subtypes includes progressive proximal muscle weakness, elevated serum creatine kinase (CK) levels, and muscle fiber atrophy (sun2025recentinsightsinto pages 5-7). Individual subtypes exhibit distinct phenotypic patterns:

LGMDD1 (DNAJB6-related): Slowly progressive proximal limb weakness with onset from the 2nd decade to upper middle age, with distal involvement. MRI shows fat infiltration, and biopsies reveal rimmed vacuoles and increased internal nuclei (sun2025recentinsightsinto pages 5-7, bouchard2023limb–girdlemusculardystrophies pages 2-4).

LGMDD2 (TNPO3-related): Highly variable presentation from infancy to late adulthood. Features include weakness of the pelvic and shoulder girdle muscles, generalized muscle atrophy, scapular winging, rigid spine, scoliosis, possible wheelchair dependence and respiratory insufficiency. Phenotypic variation is notable even within families (costa2022lgmdd2tnpo3related pages 1-2, sun2025recentinsightsinto pages 5-7).

LGMDD3 (HNRNPDL-related): Slowly progressive proximal limb weakness with adult onset. Rimmed vacuoles on muscle biopsy (sun2025recentinsightsinto pages 5-7, bouchard2023limb–girdlemusculardystrophies pages 2-4).

LGMDD4 (CAPN3 dominant): Progressive scapular and pelvic girdle degeneration with onset at 8–15 years. Severity depends on mutation type, with missense mutations causing milder phenotypes than null mutations (sun2025recentinsightsinto pages 5-7, bouchard2023limb–girdlemusculardystrophies pages 2-4).

LGMDD5 (Bethlem myopathy): Progressive weakness with proximal muscle atrophy, onset 10–30 years. Characteristic findings include ankle contractures and distinctive MRI signs ("target sign" and "sandwich sign") (bouchard2023limb–girdlemusculardystrophies pages 2-4, sun2025recentinsightsinto pages 5-7).

Caveolinopathy (CAV3, formerly LGMD1C): HyperCKemia in all patients, ankle contracture, calf hypertrophy, exercise intolerance, muscular cramps. May overlap with rippling muscle disease, familial hypertrophic cardiomyopathy, and distal myopathy phenotypes (bouchard2023limb–girdlemusculardystrophies pages 2-4).

Suggested HPO Terms

• HP:0003202 — Skeletal muscle atrophy
• HP:0003560 — Muscular dystrophy
• HP:0003325 — Limb-girdle muscle weakness
• HP:0003236 — Elevated circulating creatine kinase concentration
• HP:0001371 — Flexion contracture
• HP:0002355 — Difficulty walking
• HP:0003701 — Proximal muscle weakness
• HP:0003557 — Increased variability in muscle fiber diameter
• HP:0003198 — Myopathy
• HP:0001644 — Dilated cardiomyopathy (LMNA-related)
• HP:0001638 — Cardiomyopathy
• HP:0002093 — Respiratory insufficiency

Diagnostic Criteria

Diagnostic criteria for LGMD include: proximal or non-proximal muscle dystrophy, muscle fiber degeneration and necrosis, elevated serum CK levels, and muscle degenerative changes with fibrofatty infiltration (sun2025recentinsightsinto pages 5-7). The combination of clinical examination, muscle MRI, CK levels, muscle biopsy, and genetic testing constitutes the standard diagnostic approach. Cardiac involvement (22% of patients) and respiratory insufficiency (15.4%) should be assessed (lin2023clinicalfeaturesimaging pages 1-2).

Diagnostic Testing

Genetic Testing: Next-generation sequencing (NGS) gene panels and whole exome sequencing (WES) have become the primary diagnostic tools. A definitive molecular diagnosis was obtained in 20% of a cohort of over 25,000 individuals with neuromuscular disorders, with diagnostic yields of up to 33% for muscular dystrophies specifically (doody2024definingclinicalendpoints pages 1-2). Multigene analysis is recommended over single-gene testing given significant phenotypic overlap (doody2024definingclinicalendpoints pages 1-2).

Biomarkers: Circulating miR-206 is a potential biomarker for disease progression, with significant elevation in LGMD patients compared to controls and 50–80-fold overexpression in severe cases (lin2023clinicalfeaturesimaging pages 1-2). MiR-1, miR-133a, and miR-206 are differentially expressed in serum and muscle, changing according to degrees of inflammation, fibrosis, and dystrophic progression (lin2023clinicalfeaturesimaging pages 1-2).

Muscle Imaging: MRI reveals fatty infiltration and replacement in affected muscles. Each subtype has characteristic patterns of muscle involvement on imaging (bouchard2023limb–girdlemusculardystrophies pages 2-4).

4. Genetic/Molecular Information

Causal Genes and Pathogenic Variants

The following table provides a comprehensive overview of the molecular mechanisms underlying each AD-LGMD subtype:

Table: This table summarizes the main pathogenic mechanisms reported for autosomal dominant limb-girdle muscular dystrophy subtypes and historically associated dominant LGMD entities. It is useful for comparing whether disease biology is driven primarily by proteostasis failure, nuclear transport defects, membrane/caveola dysfunction, cytoskeletal aggregation, or extracellular matrix disruption.

LGMDD1 (DNAJB6) — Detailed Molecular Mechanism

DNAJB6 exists as two isoforms: the nuclear isoform DNAJB6a and the cytoplasmic isoform DNAJB6b, with the latter being the primary pathogenic isoform (findlay2023dnajb6isoformspecific pages 1-3). Disease-causing mutations are clustered in the G/F region near the α5 helix and in the J domain (sarparanta2020neuromusculardiseasesdue pages 9-11, sarparanta2020neuromusculardiseasesdue pages 7-9).

The pathogenic mechanism is a toxic gain-of-function dependent on DNAJB6-HSP70 interaction. Wild-type DNAJB6 possesses an autoinhibitory mechanism in its G/F domain that regulates J-domain interaction with HSP70. LGMDD1 mutations disrupt this autoinhibition, making the J-domain constitutively accessible for HSP70 binding (inoue2025moleculargeneticsof pages 6-8). The mutant DNAJB6 can thus "recruit and hyperactivate Hsp70 chaperones in an unregulated manner, depleting Hsp70 levels in myocytes, and resulting in the disruption of proteostasis" (abayevavraham2023dnajb6mutantsdisplay pages 1-2). This aberrant interaction leads to abnormal trapping of HSP70 at the Z-disc, impairing its normal rapid diffusion (bengoechea2025inhibitionofdnajhsp70 pages 1-2). Accumulated proteins include structural Z-disc proteins, RNA-binding stress-granule proteins, TDP-43, and various chaperones and cochaperones (HSPA8, CRYAB, HSPB8, SQSTM1, BAG3, STUB1), indicating widespread proteostasis disruption (sarparanta2020neuromusculardiseasesdue pages 7-9).

LGMDD2 (TNPO3) — Detailed Molecular Mechanism

TNPO3 mutations produce a protein with an extended C-terminal domain that impairs nuclear transport of SR proteins essential for mRNA splicing and metabolism (rodia2025novelinsightsinto pages 1-2). Mutated TNPO3 fails to properly transport cargo proteins (SRSF1, SRSF2, RBM4, CPSF6) through the nuclear membrane, disrupting alternative splicing and protein synthesis. This leads to myofibrillar protein accumulation and disarray (costa2022lgmdd2tnpo3related pages 7-8). Recent zebrafish studies demonstrated that mutant TNPO3 caused myofibrillar disarray with perpendicularly oriented fibers resembling LGMDD2 patient muscle architecture (rodia2025novelinsightsinto pages 8-13). The mutation disrupts normal myogenic commitment and affects myogenic regulatory factor expression, representing impaired myogenesis as a core disease mechanism (rodia2025novelinsightsinto pages 18-19, rodia2025novelinsightsinto pages 5-8).

CAV3 (Caveolinopathy) — Detailed Molecular Mechanism

The P104L mutation causes dramatic loss of Cav3 protein through a dominant negative mechanism, with the mutant protein being retained in the Golgi complex and subjected to proteasomal degradation rather than trafficking to the plasma membrane (shah2020caveolin‐3deficiencyassociated pages 7-9). Cav3 deficiency impairs mTORC1 signaling by disrupting lysosomal cholesterol trafficking, increasing lysosomal cholesterol content by 26% and suppressing mTORC1 activation, with phosphorylation of S6K1 and 4EBP1 reduced by 75–90% (shah2023caveolin‐3losslinked pages 1-2). Additionally, the P104L mutation causes mitochondrial fragmentation, shifting from predominantly tubular/elongated mitochondria (~65%) to fragmented/spheroid forms (>60%), with significant reductions in oxygen consumption rates (shah2020caveolin‐3deficiencyassociated pages 7-9). Loss of Cav3 also reduces cardiolipin content, increases mitochondrial cholesterol, elevates ROS production, and impairs myoblast differentiation through reduced Akt and p38 signaling (shah2020caveolin‐3deficiencyassociated pages 1-2, shah2020caveolin‐3deficiencyassociated pages 20-20, shah2020caveolin‐3deficiencyassociated pages 16-17).

Suggested GO Terms

• GO:0006457 — Protein folding
• GO:0051085 — Chaperone cofactor-dependent protein refolding
• GO:0006606 — Protein import into nucleus
• GO:0000398 — mRNA splicing, via spliceosome
• GO:0007517 — Muscle organ development
• GO:0030240 — Skeletal muscle thin filament assembly
• GO:0045214 — Sarcomere organization
• GO:0031529 — Ruffle organization (caveolae)
• GO:0006914 — Autophagy

5. Anatomical Structures Affected

Organ Level

• Primary: Skeletal muscle (UBERON:0001134), particularly proximal limb muscles
• Secondary: Heart (UBERON:0000948) — cardiac involvement in LMNA-related and some CAV3-related forms; respiratory system (UBERON:0001004) — restrictive respiratory insufficiency in ~15.4% of patients (lin2023clinicalfeaturesimaging pages 1-2)

Tissue and Cell Level

• Skeletal muscle tissue (UBERON:0001134)
• Skeletal muscle fibers (CL:0000187 — skeletal muscle fiber)
• Myoblasts (CL:0000056 — myoblast)
• Satellite cells (CL:0000594 — skeletal muscle satellite cell)

Subcellular Level

• Z-disc (GO:0030018) — aggregation of Z-disc proteins in LGMDD1
• Sarcomere (GO:0030017)
• Nucleus (GO:0005634) — nuclear transport disruption in LGMDD2
• Mitochondria (GO:0005739) — dysfunction in CAV3-related disease
• Caveolae (GO:0005901) — disrupted in CAV3-related disease
• Sarcoplasmic reticulum and plasma membrane

6. Temporal Development

Onset

• LGMDD1: 2nd decade to upper middle age (sun2025recentinsightsinto pages 5-7)
• LGMDD2: Infancy to late adulthood, highly variable (costa2022lgmdd2tnpo3related pages 1-2, sun2025recentinsightsinto pages 5-7)
• LGMDD3: Adult onset (sun2025recentinsightsinto pages 5-7)
• LGMDD4: 8–15 years (sun2025recentinsightsinto pages 5-7)
• LGMDD5: 10–30 years (sun2025recentinsightsinto pages 5-7)

Progression

Disease course is chronic and progressive, though the rate of progression varies substantially among subtypes and even within families. Some subtypes show stability until adulthood followed by slow progression, while others demonstrate early-onset disease with more rapid deterioration (costa2022lgmdd2tnpo3related pages 1-2). Cardiac involvement may present as sudden cardiac death, as documented in a patient with LMNA-related muscular dystrophy at age 37 (lin2023clinicalfeaturesimaging pages 1-2).

7. Epidemiology and Inheritance

Epidemiology

LGMD collectively has a global incidence of approximately 0.7 per 100,000 and variable prevalence by region (doody2024definingclinicalendpoints pages 1-2). AD-LGMDs represent approximately 10–15% of all LGMDs (costa2022lgmdd2tnpo3related pages 1-2). In a US population-based study (MD STARnet, 2008–2016), LGMD was the most common diagnosis among 243 individuals with muscular dystrophy (138 cases), with a higher proportion of male individuals compared with female individuals (lin2023clinicalfeaturesimaging pages 1-2).

Inheritance Pattern

All AD-LGMD subtypes follow an autosomal dominant inheritance pattern with variable expressivity and incomplete penetrance in some subtypes (sun2025recentinsightsinto pages 5-7, costa2022lgmdd2tnpo3related pages 1-2). The expressivity varies significantly even within the same family carrying the same pathogenic variant, as documented for TNPO3 and CAV3 mutations (costa2022lgmdd2tnpo3related pages 1-2). Somatic mosaicism has been documented in parents of LMNA-related muscular dystrophy probands (lin2023clinicalfeaturesimaging pages 1-2). De novo mutations are recognized, particularly in LMNA and DNAJB6 (lin2023clinicalfeaturesimaging pages 1-2).

8. Treatment

Current Treatment — Symptomatic Management

Currently, only symptomatic treatments are available for AD-LGMD patients. Symptomatic therapy manages symptoms through interventions including nocturnal ventilation for respiratory impairment, β-blockers for cardiac involvement, nutritional adjustments, and physical rehabilitation, though it does not slow disease progression (sun2025recentinsightsinto pages 18-21). Exercise interventions, including aerobic and resistance training, have demonstrated improvements in muscle strength and cardiorespiratory function (sun2025recentinsightsinto pages 18-21). Suggested MAXO terms: MAXO:0000950 — Supportive care; MAXO:0001001 — Respiratory support.

Experimental Therapeutics

Small Molecule DNAJ-HSP70 Inhibitors (LGMDD1): Treatment with a small-molecule inhibitor (JG231) of the DNAJ-HSP70 complex restored HSP70 mobility, improved muscle strength, and corrected myopathological features in LGMDD1 mouse models (bengoechea2025inhibitionofdnajhsp70 pages 1-2). This represents a promising therapeutic avenue as "interfering with DNAJB6-Hsp70 binding reverses the disease phenotype" (abayevavraham2023dnajb6mutantsdisplay pages 9-9).

Isoform-Specific Knockdown (LGMDD1): Morpholino antisense oligonucleotides targeting the DNAJB6b isoform (BPAS morpholinos) have shown therapeutic potential. Selective DNAJB6b reduction corrected 57% of disease-related proteins toward wild-type levels in F90I+/- myotubes, including HSP70 (findlay2023dnajb6isoformspecific pages 4-5). This approach was validated in primary mouse myotubes, human LGMDD1 myoblasts, and mouse skeletal muscle in vivo (findlay2022dnajb6isoformspecific pages 1-7, findlay2022dnajb6isoformspecific pages 13-17). Future clinical translation may involve peptide-conjugated phosphorodiamidate morpholinos or AAV-delivered U7-snRNA approaches (findlay2022dnajb6isoformspecific pages 7-13).

RNAi Approaches: RNAi approaches to knock down dominant mutations, such as myotilin mutations in LGMD1A, are under investigation (bouchard2023limb–girdlemusculardystrophies pages 9-11).

Gene Editing: CRISPR-Cas systems, base editing, and prime editing approaches have been explored, with some in vitro experiments successfully correcting mutations in LGMD models (bouchard2023limb–girdlemusculardystrophies pages 9-11).

Clinical Trial Readiness: The GRASP-LGMD Research Consortium (NCT03981289) is a multi-center study of 188 LGMD patients across 13 sites, including DNAJB6/LGMDD1 patients, designed to validate clinical outcome assessments for future clinical trials (doody2024definingclinicalendpoints pages 1-2).

9. Model Organisms

LGMDD1 (DNAJB6) Models

Transgenic Mouse Model: Overexpression of mutant DNAJB6b-F93L under the MCK promoter produces an aggressive myopathy with 40% mortality by 2 months, desmin inclusions, and hnRNPA1/A2B1 aggregates recapitulating human LGMDD1 pathology (bengoechea2025inhibitionofdnajhsp70 pages 8-13).

Knock-in Mouse Model: A more physiologically relevant knock-in model expressing the LGMDD1 F90I mutation at endogenous levels develops progressive myopathy and has been used for preclinical therapeutic testing, including the DNAJ-HSP70 inhibitor JG231 (inoue2025moleculargeneticsof pages 8-10, bengoechea2025inhibitionofdnajhsp70 pages 8-13).

C. elegans Model: Blocking mutant DNAJB6-Hsp70 interaction rescues normal muscle morphology, and Hsp70 overexpression partially rescues disease phenotypes in C. elegans (abayevavraham2023dnajb6mutantsdisplay pages 9-9).

Zebrafish Model: Among the first in vivo models providing evidence that DNAJB6 mutations are pathogenic, demonstrating distinct muscle defects and implicating the cytoplasmic DNAJB6b isoform (inoue2025moleculargeneticsof pages 8-10).

LGMDD2 (TNPO3) Models

Zebrafish Model: Microinjection of zebrafish embryos with mutant human TNPO3 mRNA caused body shortening, myofibrillar disarray, altered myosin patterning, and disrupted expression of myogenic regulatory factors (rodia2025novelinsightsinto pages 8-13, rodia2025novelinsightsinto pages 2-4). The model validates that TNPO3 mutations disrupt normal myogenic commitment and provides a platform for drug testing (rodia2025novelinsightsinto pages 18-19).

C2C12 Cell Model: Transfection of C2C12 cells with mutant TNPO3 demonstrated effects on muscle regulatory factor expression, p62 (autophagy marker), MuRF-1 (muscle atrophy marker), and desmin expression (rodia2025novelinsightsinto pages 5-8, rodia2025novelinsightsinto pages 4-5).

10. Prognosis and Outcomes

Disease Course

AD-LGMDs generally follow a chronic progressive course, though the rate and severity vary markedly by subtype. LGMDD1 presents with slowly progressive proximal weakness, while LGMDD2 shows wide variability from childhood-onset with wheelchair dependence to adult-onset stable disease (costa2022lgmdd2tnpo3related pages 1-2, sun2025recentinsightsinto pages 5-7).

Complications

Cardiac abnormalities were present in 22% of patients in one cohort, and one patient with LMNA-related muscular dystrophy experienced sudden cardiac death at age 37 (lin2023clinicalfeaturesimaging pages 1-2). Restrictive respiratory insufficiency was documented in 15.4% of patients (lin2023clinicalfeaturesimaging pages 1-2). Joint contractures, scoliosis, and scapular winging are common skeletal complications (costa2022lgmdd2tnpo3related pages 1-2, bouchard2023limb–girdlemusculardystrophies pages 2-4).

Life Expectancy

Life expectancy varies by subtype. Most AD-LGMD forms have near-normal lifespan when cardiac involvement is monitored and managed, though LMNA-related forms carry risk of life-threatening cardiac arrhythmias. Specific longevity data for individual AD-LGMD subtypes remain limited.

11. Prevention

Primary Prevention

As monogenic disorders, AD-LGMDs cannot be prevented through lifestyle modification. Primary prevention relies on genetic counseling and family planning.

Genetic Counseling and Screening

Given autosomal dominant inheritance, affected individuals have a 50% risk of transmitting the disease to offspring. Genetic counseling is recommended for all affected families. Preimplantation genetic diagnosis (PGD) and prenatal testing are available when the familial mutation is known. Cascade genetic testing of at-risk family members is recommended.

Secondary Prevention

Cardiac surveillance is essential for LMNA-related forms due to high risk of arrhythmias and sudden death. Regular respiratory function monitoring is recommended for all subtypes given the ~15% rate of restrictive pulmonary insufficiency (lin2023clinicalfeaturesimaging pages 1-2).

12. Summary and Current Challenges

AD-LGMD remains a diagnostic and therapeutic challenge due to its genetic heterogeneity, phenotypic variability, and rarity. The 2018 reclassification streamlined the nomenclature to five recognized subtypes (LGMDD1–D5), though several historically classified forms (MYOT, LMNA, CAV3, DES) remain clinically important entities that have been reclassified to other disease categories (jeong2023tripartitemotifcontainingprotein pages 10-11). The most promising therapeutic advances center on LGMDD1 (DNAJB6-related), where both small molecule inhibitors of the DNAJ-HSP70 interaction and isoform-specific antisense oligonucleotide knockdown approaches have shown preclinical efficacy (bengoechea2025inhibitionofdnajhsp70 pages 1-2, findlay2023dnajb6isoformspecific pages 4-5, findlay2023dnajb6isoformspecific pages 1-3). The GRASP-LGMD consortium represents a critical infrastructure development for clinical trial readiness (doody2024definingclinicalendpoints pages 1-2). Despite these advances, no disease-modifying therapies are yet available for human patients with any AD-LGMD subtype, and treatment remains supportive.

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14. (abayevavraham2023dnajb6mutantsdisplay pages 9-9): Meital Abayev-Avraham, Yehuda Salzberg, Dar Gliksberg, Meital Oren-Suissa, and Rina Rosenzweig. Dnajb6 mutants display toxic gain of function through unregulated interaction with hsp70 chaperones. Nature Communications, Nov 2023. URL: https://doi.org/10.1038/s41467-023-42735-z, doi:10.1038/s41467-023-42735-z. This article has 47 citations and is from a highest quality peer-reviewed journal.

15. (abayevavraham2023dnajb6mutantsdisplay pages 1-2): Meital Abayev-Avraham, Yehuda Salzberg, Dar Gliksberg, Meital Oren-Suissa, and Rina Rosenzweig. Dnajb6 mutants display toxic gain of function through unregulated interaction with hsp70 chaperones. Nature Communications, Nov 2023. URL: https://doi.org/10.1038/s41467-023-42735-z, doi:10.1038/s41467-023-42735-z. This article has 47 citations and is from a highest quality peer-reviewed journal.

16. (bengoechea2025inhibitionofdnajhsp70 pages 7-8): R. Bengoechea, Andrew R. Findlay, Ankan K. Bhadra, Hao Shao, Kevin C. Stein, S. Pittman, J. Daw, Jason E. Gestwicki, Heather L. True, and Conrad C. Weihl. Inhibition of dnaj-hsp70 interaction improves strength in muscular dystrophy. The Journal of Clinical Investigation, May 2025. URL: https://doi.org/10.1172/jci194757, doi:10.1172/jci194757. This article has 48 citations.

17. (sarparanta2020neuromusculardiseasesdue pages 7-9): J. Sarparanta, P. Jonson, S. Kawan, and B. Udd. Neuromuscular diseases due to chaperone mutations: a review and some new results. International Journal of Molecular Sciences, Feb 2020. URL: https://doi.org/10.3390/ijms21041409, doi:10.3390/ijms21041409. This article has 91 citations.

18. (rodia2025novelinsightsinto pages 18-19): MT Rodia, M. Fazzina, Roberta Costa, MT Altieri, G. Sabbioni, E. D’Aversa, G. Breveglieri, E. Gatto, C. Bertolucci, S. Lombardi, M. Bergonzoni, R. Casadei, S. Santi, V. Papa, S. Ratti, G. Cenacchi, M. Borgatti, and F. Frabetti. Novel insights into the molecular mechanisms of lgmdd2: role of tnpo3 in experimental cell and zebrafish models. Cellular and Molecular Life Sciences, Nov 2025. URL: https://doi.org/10.1007/s00018-025-05954-9, doi:10.1007/s00018-025-05954-9. This article has 0 citations and is from a domain leading peer-reviewed journal.

19. (rodia2025novelinsightsinto pages 8-13): MT Rodia, M. Fazzina, Roberta Costa, MT Altieri, G. Sabbioni, E. D’Aversa, G. Breveglieri, E. Gatto, C. Bertolucci, S. Lombardi, M. Bergonzoni, R. Casadei, S. Santi, V. Papa, S. Ratti, G. Cenacchi, M. Borgatti, and F. Frabetti. Novel insights into the molecular mechanisms of lgmdd2: role of tnpo3 in experimental cell and zebrafish models. Cellular and Molecular Life Sciences, Nov 2025. URL: https://doi.org/10.1007/s00018-025-05954-9, doi:10.1007/s00018-025-05954-9. This article has 0 citations and is from a domain leading peer-reviewed journal.

20. (rodia2025novelinsightsinto pages 5-8): MT Rodia, M. Fazzina, Roberta Costa, MT Altieri, G. Sabbioni, E. D’Aversa, G. Breveglieri, E. Gatto, C. Bertolucci, S. Lombardi, M. Bergonzoni, R. Casadei, S. Santi, V. Papa, S. Ratti, G. Cenacchi, M. Borgatti, and F. Frabetti. Novel insights into the molecular mechanisms of lgmdd2: role of tnpo3 in experimental cell and zebrafish models. Cellular and Molecular Life Sciences, Nov 2025. URL: https://doi.org/10.1007/s00018-025-05954-9, doi:10.1007/s00018-025-05954-9. This article has 0 citations and is from a domain leading peer-reviewed journal.

21. (costa2022lgmdd2tnpo3related pages 5-7): Roberta Costa, Maria Teresa Rodia, Serafina Pacilio, Corrado Angelini, and Giovanna Cenacchi. Lgmd d2 tnpo3-related: from clinical spectrum to pathogenetic mechanism. Frontiers in Neurology, Mar 2022. URL: https://doi.org/10.3389/fneur.2022.840683, doi:10.3389/fneur.2022.840683. This article has 27 citations and is from a peer-reviewed journal.

22. (shah2023caveolin‐3losslinked pages 1-2): Dinesh S. Shah, Raid B. Nisr, Gabriela Krasteva‐Christ, and Harinder S. Hundal. Caveolin‐3 loss linked with the p104l lgmd‐1c mutation modulates skeletal muscle mtorc1 signalling and cholesterol homeostasis. Journal of Cachexia, Sarcopenia and Muscle, 14:2310-2326, Sep 2023. URL: https://doi.org/10.1002/jcsm.13317, doi:10.1002/jcsm.13317. This article has 6 citations and is from a domain leading peer-reviewed journal.

23. (shah2020caveolin‐3deficiencyassociated pages 1-2): Dinesh S. Shah, Raid B. Nisr, Clare Stretton, Gabriela Krasteva‐Christ, and Harinder S. Hundal. Caveolin‐3 deficiency associated with the dystrophy p104l mutation impairs skeletal muscle mitochondrial form and function. Journal of Cachexia, Sarcopenia and Muscle, 11:838-858, Feb 2020. URL: https://doi.org/10.1002/jcsm.12541, doi:10.1002/jcsm.12541. This article has 40 citations and is from a domain leading peer-reviewed journal.

24. (shah2020caveolin‐3deficiencyassociated pages 7-9): Dinesh S. Shah, Raid B. Nisr, Clare Stretton, Gabriela Krasteva‐Christ, and Harinder S. Hundal. Caveolin‐3 deficiency associated with the dystrophy p104l mutation impairs skeletal muscle mitochondrial form and function. Journal of Cachexia, Sarcopenia and Muscle, 11:838-858, Feb 2020. URL: https://doi.org/10.1002/jcsm.12541, doi:10.1002/jcsm.12541. This article has 40 citations and is from a domain leading peer-reviewed journal.

25. (shah2020caveolin‐3deficiencyassociated pages 20-20): Dinesh S. Shah, Raid B. Nisr, Clare Stretton, Gabriela Krasteva‐Christ, and Harinder S. Hundal. Caveolin‐3 deficiency associated with the dystrophy p104l mutation impairs skeletal muscle mitochondrial form and function. Journal of Cachexia, Sarcopenia and Muscle, 11:838-858, Feb 2020. URL: https://doi.org/10.1002/jcsm.12541, doi:10.1002/jcsm.12541. This article has 40 citations and is from a domain leading peer-reviewed journal.

26. (shah2020caveolin‐3deficiencyassociated pages 16-17): Dinesh S. Shah, Raid B. Nisr, Clare Stretton, Gabriela Krasteva‐Christ, and Harinder S. Hundal. Caveolin‐3 deficiency associated with the dystrophy p104l mutation impairs skeletal muscle mitochondrial form and function. Journal of Cachexia, Sarcopenia and Muscle, 11:838-858, Feb 2020. URL: https://doi.org/10.1002/jcsm.12541, doi:10.1002/jcsm.12541. This article has 40 citations and is from a domain leading peer-reviewed journal.

27. (shah2020caveolin‐3deficiencyassociated pages 19-20): Dinesh S. Shah, Raid B. Nisr, Clare Stretton, Gabriela Krasteva‐Christ, and Harinder S. Hundal. Caveolin‐3 deficiency associated with the dystrophy p104l mutation impairs skeletal muscle mitochondrial form and function. Journal of Cachexia, Sarcopenia and Muscle, 11:838-858, Feb 2020. URL: https://doi.org/10.1002/jcsm.12541, doi:10.1002/jcsm.12541. This article has 40 citations and is from a domain leading peer-reviewed journal.

28. (findlay2023dnajb6isoformspecific pages 1-3): Andrew R. Findlay, May M. Paing, Jil A. Daw, Meade Haller, Rocio Bengoechea, Sara K. Pittman, Shan Li, Feng Wang, Timothy M. Miller, Heather L. True, Tsui-Fen Chou, and Conrad C. Weihl. Dnajb6 isoform specific knockdown: therapeutic potential for limb girdle muscular dystrophy d1. Molecular Therapy - Nucleic Acids, 32:937-948, Jun 2023. URL: https://doi.org/10.1016/j.omtn.2023.05.017, doi:10.1016/j.omtn.2023.05.017. This article has 10 citations.

29. (inoue2025moleculargeneticsof pages 6-8): Michio Inoue. Molecular genetics of j-domain protein-related chaperonopathies in skeletal muscle. Journal of human genetics, Jul 2025. URL: https://doi.org/10.1038/s10038-025-01372-8, doi:10.1038/s10038-025-01372-8. This article has 0 citations and is from a peer-reviewed journal.

30. (findlay2023dnajb6isoformspecific pages 4-5): Andrew R. Findlay, May M. Paing, Jil A. Daw, Meade Haller, Rocio Bengoechea, Sara K. Pittman, Shan Li, Feng Wang, Timothy M. Miller, Heather L. True, Tsui-Fen Chou, and Conrad C. Weihl. Dnajb6 isoform specific knockdown: therapeutic potential for limb girdle muscular dystrophy d1. Molecular Therapy - Nucleic Acids, 32:937-948, Jun 2023. URL: https://doi.org/10.1016/j.omtn.2023.05.017, doi:10.1016/j.omtn.2023.05.017. This article has 10 citations.

31. (findlay2022dnajb6isoformspecific pages 1-7): Andrew R. Findlay, May M. Paing, Jil A. Daw, Rocio Bengoechea, Sara K. Pittman, Shan Li, Feng Wang, Timothy M. Miller, Heather L. True, Tsui-Fen Chou, and Conrad C. Weihl. Dnajb6 isoform specific knockdown: therapeutic potential for lgmdd1. bioRxiv, Nov 2022. URL: https://doi.org/10.1101/2022.11.17.516920, doi:10.1101/2022.11.17.516920. This article has 1 citations.

32. (findlay2022dnajb6isoformspecific pages 13-17): Andrew R. Findlay, May M. Paing, Jil A. Daw, Rocio Bengoechea, Sara K. Pittman, Shan Li, Feng Wang, Timothy M. Miller, Heather L. True, Tsui-Fen Chou, and Conrad C. Weihl. Dnajb6 isoform specific knockdown: therapeutic potential for lgmdd1. bioRxiv, Nov 2022. URL: https://doi.org/10.1101/2022.11.17.516920, doi:10.1101/2022.11.17.516920. This article has 1 citations.

33. (findlay2022dnajb6isoformspecific pages 7-13): Andrew R. Findlay, May M. Paing, Jil A. Daw, Rocio Bengoechea, Sara K. Pittman, Shan Li, Feng Wang, Timothy M. Miller, Heather L. True, Tsui-Fen Chou, and Conrad C. Weihl. Dnajb6 isoform specific knockdown: therapeutic potential for lgmdd1. bioRxiv, Nov 2022. URL: https://doi.org/10.1101/2022.11.17.516920, doi:10.1101/2022.11.17.516920. This article has 1 citations.

34. (bouchard2023limb–girdlemusculardystrophies pages 9-11): Camille Bouchard and Jacques P. Tremblay. Limb–girdle muscular dystrophies classification and therapies. Journal of Clinical Medicine, 12:4769, Jul 2023. URL: https://doi.org/10.3390/jcm12144769, doi:10.3390/jcm12144769. This article has 73 citations.

35. (bengoechea2025inhibitionofdnajhsp70 pages 8-13): R. Bengoechea, Andrew R. Findlay, Ankan K. Bhadra, Hao Shao, Kevin C. Stein, S. Pittman, J. Daw, Jason E. Gestwicki, Heather L. True, and Conrad C. Weihl. Inhibition of dnaj-hsp70 interaction improves strength in muscular dystrophy. The Journal of Clinical Investigation, May 2025. URL: https://doi.org/10.1172/jci194757, doi:10.1172/jci194757. This article has 48 citations.

36. (inoue2025moleculargeneticsof pages 8-10): Michio Inoue. Molecular genetics of j-domain protein-related chaperonopathies in skeletal muscle. Journal of human genetics, Jul 2025. URL: https://doi.org/10.1038/s10038-025-01372-8, doi:10.1038/s10038-025-01372-8. This article has 0 citations and is from a peer-reviewed journal.

37. (rodia2025novelinsightsinto pages 2-4): MT Rodia, M. Fazzina, Roberta Costa, MT Altieri, G. Sabbioni, E. D’Aversa, G. Breveglieri, E. Gatto, C. Bertolucci, S. Lombardi, M. Bergonzoni, R. Casadei, S. Santi, V. Papa, S. Ratti, G. Cenacchi, M. Borgatti, and F. Frabetti. Novel insights into the molecular mechanisms of lgmdd2: role of tnpo3 in experimental cell and zebrafish models. Cellular and Molecular Life Sciences, Nov 2025. URL: https://doi.org/10.1007/s00018-025-05954-9, doi:10.1007/s00018-025-05954-9. This article has 0 citations and is from a domain leading peer-reviewed journal.

38. (rodia2025novelinsightsinto pages 4-5): MT Rodia, M. Fazzina, Roberta Costa, MT Altieri, G. Sabbioni, E. D’Aversa, G. Breveglieri, E. Gatto, C. Bertolucci, S. Lombardi, M. Bergonzoni, R. Casadei, S. Santi, V. Papa, S. Ratti, G. Cenacchi, M. Borgatti, and F. Frabetti. Novel insights into the molecular mechanisms of lgmdd2: role of tnpo3 in experimental cell and zebrafish models. Cellular and Molecular Life Sciences, Nov 2025. URL: https://doi.org/10.1007/s00018-025-05954-9, doi:10.1007/s00018-025-05954-9. This article has 0 citations and is from a domain leading peer-reviewed journal.

Artifacts

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• Edison artifact artifact-01