| Subtype | Gene/Protein | Mechanism Type | Key Molecular Pathways Affected | Cellular Processes Disrupted | Key References |
|---|---|---|---|---|---|
| LGMDD1 (formerly LGMD1D) | **DNAJB6** / DnaJ heat shock protein family member B6 | **Toxic gain-of-function** | Hsp70 chaperone cycle dysregulation; proteostasis network; Z-disc protein quality control; autophagy-related stress pathways | Unregulated DNAJB6-Hsp70 binding, Hsp70 sequestration/depletion, protein misfolding, myofibrillar/Z-disc aggregation, vacuolar myopathy | (pqac-00000007, pqac-00000009, pqac-00000010, pqac-00000011, pqac-00000012, pqac-00000014) |
| LGMDD2 (formerly LGMD1F) | **TNPO3** / Transportin-3 | **Likely dominant toxic / loss-of-function mechanism** | Nuclear import of SR proteins; RNA metabolism and alternative splicing; myogenic regulatory factor signaling; autophagy | Impaired nuclear transport of splicing factors (e.g., SRSF1/SRSF2/RBM4/CPSF6), altered transcript processing, abnormal myogenic commitment, myofibrillar disarray, myofiber atrophy | (pqac-00000038, pqac-00000039, pqac-00000040, pqac-00000041, pqac-00000043, pqac-00000045) |
| LGMD1C / caveolinopathy (excluded from revised LGMD classification) | **CAV3** / Caveolin-3 | **Dominant negative with functional Caveolin-3 deficiency** | Caveolae biology; mTORC1 signaling; lysosomal cholesterol trafficking; mitochondrial homeostasis; Akt/p38 signaling | Caveolin-3 loss, reduced anabolic signaling, impaired protein synthesis, mitochondrial fragmentation and respiratory failure, altered cholesterol distribution, defective myoblast differentiation/fusion | (pqac-00000015, pqac-00000016, pqac-00000017, pqac-00000018, pqac-00000019, pqac-00000020) |
| LGMD1A / myotilinopathy (excluded from revised LGMD classification) | **MYOT** / Myotilin | **Unclear; dominant structural/protein-aggregation mechanism** | Sarcomere assembly; actin filament cross-linking; Z-disc organization | Disrupted actin cross-linking, impaired sarcomere assembly, myofibrillar instability, protein aggregate formation | (pqac-00000005, pqac-00000006) |
| LGMD1B / laminopathy (excluded from revised LGMD classification) | **LMNA** / Lamin A/C | **Predominantly dominant negative / structural nuclear envelope dysfunction** | Nuclear lamina integrity; mechanotransduction; genome organization and transcriptional regulation | Nuclear envelope disruption, abnormal nuclear morphology, muscle fiber fragility, conduction-system/cardiac involvement in many patients | (pqac-00000001, pqac-00000005, pqac-00000006) |
| LGMD1E / desminopathy (excluded from revised LGMD classification) | **DES** / Desmin | **Dominant protein-aggregation / filament disorganization mechanism** | Intermediate filament network; cytoskeletal organization; myofibril integrity | Desmin aggregation, irregular muscle fiber architecture, cytoskeletal collapse, myofibrillar degeneration | (pqac-00000001, pqac-00000005, pqac-00000006) |
| LGMDD3 (formerly LGMD1G) | **HNRNPDL** / hnRNP D-like | **Likely dominant toxic protein/RNA-processing mechanism** | RNA binding and transcription/splicing regulation | Abnormal RNA handling, rimmed-vacuolar myopathy, progressive proximal weakness | (pqac-00000000, pqac-00000001, pqac-00000003, pqac-00000004) |
| LGMDD4 (formerly LGMD1I) | **CAPN3** / Calpain-3 | **Mutation-dependent; dominant pathogenic mechanism recognized but incompletely defined** | Sarcomere remodeling; muscle proteolysis; myofibrillar maintenance | Scapular/pelvic girdle degeneration, impaired sarcomeric maintenance, progressive muscle fiber loss | (pqac-00000000, pqac-00000001, pqac-00000003, pqac-00000004) |
| LGMDD5 (Bethlem myopathy spectrum) | **COL6A1/COL6A2/COL6A3** / Collagen VI | **Usually dominant structural extracellular-matrix mechanism** | Extracellular matrix organization; basement membrane-matrix interactions; muscle regeneration support | Matrix instability, impaired muscle fiber support, proximal weakness, contractures/ankle contracture, progressive fatty replacement | (pqac-00000003, pqac-00000004, pqac-00000025, pqac-00000026) |


*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.*