Table 1 Limb Girdle Muscular Dystrophy (LGMD) classification (Argente-Escrig et al. 2021; Arvio et al. 2019; Beckmann and Spencer 2008; Benarroch et al. 2024; Bonnemann 2011; Cenacchi et al. 2013; Chompoopong and Milone 2023; Coppens et al. 2021; Dai et al. 2019; De Ridder et al. 2023; Endo et al. 2015; Finsterer 2018; Gaertner et al. 2022; Geis et al. 2019; Guan et al. 2023; Huang et al. 2023; Lampe and Bushby 2005; Li et al. 2023; Lv et al. 2021; Mahmood et al. 2023; Melia et al., 2013; Meyer et al. 2022; Morales-Rosado et al. 2023; Mroczek et al. 2020; Munot et al. 2022; Murphy and Straub 2015; Palenzuela et al. 2003; Panicucci et al. 2023; Saenz et al., 2005; Sandell et al. 2016; Savarese et al. 2020; Soontrapa and Liewluck 2022; Starling et al. 2004; Straub et al. 2018; Vainzof et al. 2021; van Tol et al. 2019; Vargas‐Franco et al., 2022; Vieira et al. 2014;Wang et al. 2022; Xie et al. 2019; Yang et al. 2021; Yogev et al. 2023; Zatz and Starling 2005; Zhou et al. 2022)

LGMD R1 calpain3-related

CAPN3, Calpain 3 (15q15.1-q21.1): proteolytic calcium-activated enzyme that in its inactive form is anchored in the titin filaments (protein that contributes to the stability of the sarcomere during contraction). It is believed that is is important for sarcomere repair and maintenance (Beckmann and Spencer 2008; Benarroch et al. 2024; Murphy and Straub 2015; Saenz et al. 2005; Straub et al. 2018; Zatz and Starling 2005)

LGMD2A

LGMD R2 dysferlin-related

DYSF, Dysferlin (2p12-14): regulation of vesicle fusion, repair of damaged membranes, T-tubule formation, calcium signaling pathway, cell adhesion (Murphy and Straub 2015; Wang et al. 2022)

LGMD2B

LGMD R3 α-sarcoglycan related

SGCA, Alpha sarcoglycan (17q21): structural function of stabilization of the dystroglycan associated complex connecting the sarcolemma to the extracellular matrix during myofibre contraction and cellular signaling (Murphy and Straub 2015; Vainzof et al. 2021)

LGMD2D

LGMD R4 β-sarcoglycan related

SGCB, Beta sarcoglycan (4q12): structural function of stabilization of the dystroglycan associated complex connecting the sarcolemma to the extracellular matrix during myofibre contraction and cellular signaling (Murphy and Straub 2015; Vainzof et al. 2021)

LGMD2E

LGMD R5

γ-sarcoglycan related

SGCG, Gamma sarcoglycan (13q12): structural function of stabilization of the dystroglycan associated complex connecting the sarcolemma to the extracellular matrix during myofibre contraction and cellular signaling (Murphy and Straub 2015; Vainzof et al. 2021)

LGMD2C

LGMD R6

δ-sarcoglycan related

SGCD, Delta-sarcoglycan (5q33-q34): structural function of stabilization of the dystroglycan associated complex connecting the sarcolemma to the extracellular matrix during myofibre contraction and cellular signaling (Murphy and Straub 2015; Vainzof et al. 2021)

LGMD2F

LGMD R7 telethonin-related

TCAP, Telethonin (titin cap) (17q12): binds to titin; involved in T tubule organization involved in sarcomere assembly and development, sarcomere-membrane interaction and signaling (Murphy and Straub 2015; Lv et al. 2021)

LGDM2G

LGMD R8 TRIM32-related

TRIM32, Tripartite motif-containing 32 (9q33.2): it binds to myosin; it may ubiquinate actin as a E3 ubiquitin ligase, i.e., a protein that attaches the lysine site of a substrate to the N-terminal methionine 1 (Met1) site that promotes adequate protein folding (Murphy and Straub 2015; Yang et al. 2021; Guan et al. 2023)

LGMD2H

LGMD R9 FKRP-related

FKRP, Fukutin-related protein (19q13.32): it is involved in O-mannose glycosylation of alpha-dystroglycan that is important for membrane stabilization during contraction (Murphy and Straub 2015; Xie et al. 2019)

LGMD2I

LGMD R10 titin-related

TTN, Titin (2q31): is the largest known human protein that connects the Z disk to the M line in the sarcomere, it presents multiple binding sites for other proteins, and it maintains the sarcomeric integrity acting as a molecular spring generating passive force (Murphy and Straub 2015; Savarese et al. 2020)

LGMD2J

LGMD R11 POMT1-related

POMT1, Protein-O-mannosyltransferase 1 (9q34.1): it is involved in the first step of glycosylation of alpha-dystroglycan acting as a glycosyltransferase that catalyses the transfer of the O-mannose residue to a Serine or Threonine residue. This is important for membrane stabilization during contraction necessary for the binding of alpha-dystroglycan to the extracelular matrix components such as laminin, perlecan, and agrin (Murphy and Straub 2015; Geis et al. 2019)

LGMD2K

LGMD R12 anoctamin5-related

ANO5, Anoctamin 5 (11p14-12): is also known as TMEM16E (transmembrane protein 16E) that is located in the sarcoplasmic reticulum and in intracellular vesicles that facilitates the movement of phospholipids between the two layers of the sarcolemma in a process called phospholipid scrambling; it is also involved in repair of the sarcolemma such as dysferlin (Soontrapa and Liewluck 2022)

LGMD2L

LGMD R13 Fukutin-related

FKTN, Fukutin (9q31-q33): it is a protein located in the Golgi apparatus that functions as a ribitol 5-phosphate transferase that is essential for the functions of the alpha-dystroglycan that is important for the connection between the membrane and proteins of the extracellular matrix fundamental for the stabilization during contraction (Murphy and Straub 2015; Gaertner et al. 2022)

LGMD2M

LGMD R14 POMT2-related

POMT2, Protein-O-mannosyltransferase 2 (14q24.3): it is involved in the glycosylation of alpha-dystroglycan that is important for membrane stabilization during contraction (Murphy and Straub 2015; Panicucci et al. 2023)

LGMD2N

LGMD R15 POMGnT1-related

POMGNT1, O-linked mannose beta1,2-N-acetylglucosaminyltransferase (1p34.1): it is involved in the glycosylation of alpha-dystroglycan that is important for membrane stabilization during contraction (Murphy and Straub 2015; Arvio et al. 2019)

LGMD2O

LGMD R16 a-dystroglycan-related

DAG1, Dystroglycan 1 (3p21): it is a basement membrane receptor that links dystrophin to proteins of the extracelullar matrix providing mechanical support to the intracellular cytoskeleton during contraction, and it has also signaling functions (Murphy and Straub 2015; Dai et al. 2019)

LGMD2P

LGMD R17 plectin-related

PLEC, Plectin (8q24.3): it is a structural protein that organizes the filamentous cytoskeletal networks linking the sarcomere to the sarcolemma with biomechanical stress-bearing properties, it also interacts with rapsyn at the neuromuscular junction (Murphy and Straub 2015; Mroczek et al. 2020; Argente-Escrig et al. 2021)

LGMD2Q

LGMD R18 TRAPPC11-related

TRAPPC11, Trafficking protein particle complex 11 (4q35.1): it is a complex that facilitates intracellular transport from the endoplasmic reticulum to the Golgi apparatus and it is also involved in autophagy (Munot et al. 2022)

LGMD2S

LGMD R19 GMPPB-related

GMPPB, GDP-mannose pyrophosphorylase B (3p21.31): it is a cytoplasmic enzyme that catalyzes the formation of GDP_mannose that is necessary of O-mannosylation of alpha-dystroglycan that is important for membrane stabilization during contraction; it participates in the glycosylation of the acetylcholine receptor sub-units necessary for proper neuromuscular junction function (Chompoopong and Milone 2023)

LGMD2T

LGMD R20 CRPPA-related

CRPPA (former ISPD), Isoprenoid synthase domain containing protein (7p21.2-p21.1): it synthesizes CDP-ribitol that is added to alpha-dystroglycan by the glycosyltransferases fukutin and fukutin-related protein; therefore it is important for the O-mannosylation of alpha dystroglycan necessary for the connection between the membrane, and the extracellular matrix proteins (van Tol et al. 2019)

LGMD2U

LGMD R21 POGLUT1-related

POGLUT1, Protein O-Glucosyltransferase 1 (3q13.33): it glycosylates the extracellular domain of Notch receptors generated in the endoplasmic reticulum, and translocated into the Golgi; it regulates skeletal muscle development, and regeneration (Murphy and Straub 2015; Vargas‐Franco et al., 2022; Zhou et al. 2022)

LGMD2Z

LGMD R22 collagen 6-related

COL6A1, Alpha 1 type VI collagen (21q22.3), COL6A2, Alpha 2 type VI collagen (21q22.3), and

COL6A3, Alpha 3 type VI collagen (2q37): it is believed that collagen VI myofibrils participate in anchorage of the basal membrane in the subjacent connective tissue; it interacts with other proteins of the extracellular matrix for maintenance and homeostasis; it participates in repair processes, development and the architecture of the muscle fibre; collagen VI associates with the basement membrane in the muscle, cartilage, periosteum, ligaments, skin, and tendon (Lampe and Bushby 2005; Bonnemann 2011; Li et al. 2023)

Bethlem myopathy

LGMD R23 laminin α2-related

LAMA2, Laminin alpha 2 chain of merosin (6q22-q23): its N-terminal domain is important for the connection between the basal lamina and the C-terminal domain binding to integrin-alpha7beta1 and the dystroglycan protein complex; it is expressed in skeletal muscle, brain, Schwann cells, synaptic basal lamina of peripheral nerves, heart, and skin (Meyer et al. 2022; Huang et al. 2023)

Merosinopathy

LGMD R24 POMGNT2-related

POMGNT2, Protein O-linked mannose N-acetylglucosaminyltransferase 2 (3p22.1): it is an endoplasmic reticulum-resident protein that catalyzes the O-mannosyl glycosylation of alpha dystroglycan to produce functional laminin-binding glycans important for membrane stabilization during contraction (Murphy and Straub 2015; Endo et al. 2015)

POMGNT2

LGMD R25 BVES-related

BVES, Blood vessel epicardial substance (6q21) (also known as POPDC1, Popeye domain-containing protein 1) (6q21): it is a transmembrane protein and a cAMP effector that is important for skeletal muscle function and homeostasis (Mahmood et al. 2023)

LGMD2X

LGMD R26 POPDC3-related

POPDC3, Popeye domain-containing protein 3 (6q21): it is a cAMP-binding transmembrane protein that is important for skeletal muscle function, and homeostasis (De Ridder et al. 2023)

POPDC3

LGMD R27 JAG2-related

JAG2, Jagged 2 (14q32.33): Jagged 2 is a Notch ligand that contributes to the development, and homeostasis of skeletal muscle, and various tissues; Notch receptors are generated in the endoplasmic reticulum and translocated in to the Golgi apparatus (Coppens et al. 2021; Zhou et al. 2022)

JAGGED2

LGMD R28 HMGCR-related

HMGCR, 3-Hydroxy-3-methylglutaryl-CoA reductase (5q13.3): HMGCR is an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, and binds to the endoplasmic reticulum membrane (Morales-Rosado et al. 2023; Yogev et al. 2023)

HMGCR

LGMD D1 DNAJB6-related

DNAJB6, HSP-40 homologue subfamily B, number 6 (7q36): it interacts with chaperones to assist autophagy and to maintain sarcomere structure (Benarroch et al. 2024; Finsterer 2018; Sandell et al. 2016; Straub et al. 2018)

LGMD1D

LGMD D2 TNPO3-related

TNPO3, Transportin 3 (7q32.1-q32.2): nuclear membrane protein that transports serine and arginine rich aminoacids to the inside of the nucleus to control the mRNA division; it is believed that aberrant proteins may interfere with nuclear protein importation and exportation resulting in disarrangement of the desmin associated cytoskeleton (Cenacchi et al. 2013; Benarroch et al. 2024; Melia et al., 2013; Palenzuela et al. 2003; Straub et al. 2018)

LGMD1F

LGMD D3 HNRNPDL-related

HNRNPDL, Heterogeneous nuclear ribonucleoprotein D-like (4q21): it participates in mRNA biogenesis, and metabolism; it is believed that it is involved in muscular development (Benarroch et al. 2024; Starling et al. 2004; Straub et al. 2018; Vieira et al. 2014)

LGMD1G

LGMD D4 calpain3-related

CAPN3, Calpain 3 (15q15.1-q21.1): proteolytic calcium-activated enzyme that in its inactive form is anchored in the titin filaments (protein that contributes to the stability of the sarcomere during contraction). It is believed that it is important for sarcomere repair and maintenance (Beckmann and Spencer 2008; Saenz et al., 2005; Zatz and Starling 2005; Murphy and Straub 2015)

LGMD1I

LGMD D5 collagen 6-related

COL6A1, Alpha 1 type VI collagen (21q22.3), COL6A2, Alpha 2 type VI collagen (21q22.3), and

COL6A3, Alpha 3 type VI collagen (2q37): it is believed that collagen VI myofibrils participate in anchorage of the basal membrane in the subjacent connective tissue; it interacts with other proteins of the extracellular matrix for maintenance and homeostasis; it participates in repair processes, development, and the architecture of the muscle fibre; collagen VI associates with the basement membrane in the muscle, cartilage, periosteum, ligaments, skin, and tendon (Lampe and Bushby 2005; Bonnemann 2011; Li et al. 2023)

Bethlem