What causes limb-girdle muscular dystrophy (LGMD)?

Updated: Aug 15, 2019
  • Author: Monica Saini, MD, MBBS, MRCP(UK); Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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LGMD2A is caused by mutations in the calpain-3 gene (CAPN3) that encodes a Ca2+-dependent nonlysosomal cysteine protease. The calpain-3 isoform is a homodimer that is abundant in skeletal muscle. More than 450 distinct pathological mutations have been identified so far. Many types of mutations have been found including nonsense mutations leading to stop codons, missense mutations often leading to decreased catalytic activity of calpain-3, splice site mutations, and small deletions or insertions.

  • In general, null mutations give rise to phenotypes more severe than those due to missense mutations.

  • CAPN3 (p94) is a member of the calpain family of intracellular, soluble cysteine proteases, most of which have calcium-dependent activation (CAPN3 is not calcium-activated). It is expressed almost exclusively in muscle and is anchored by titin at the M-line and N2 line (within the I-band of the sarcomere).

  • CAPN3 is involved in cleavage and/or breakdown of several proteins, particularly those involved in assembly and scaffolding of myofibrillar proteins including titin, vinculin, C-terminal binding protein 1, and filamin C.

  • CAPN3 also has thiol-dependent proteolytic activity directed against the skeletal muscle ryanodine receptor (RyR). RyR is a Ca2+-release channel, and lack of regulation of RyR by CAPN3 may play a role in skeletal muscle dysfunction.

  • Mutations in the CAPN3 gene can lead directly to loss of proteolytic activity or to secondary loss of activity due to its loss of anchorage with titin. The loss of proteolytic activity may lead to reduced cleavage of cytoskeletal and myofibrillar proteins, decreased ubiquitination, and proteasome-mediated degradation, accumulation of damaged proteins that then accumulate within muscle.

  • How the absence of CAPN3 triggers an initial event that leads to metabolic reprogramming in the muscle is not entirely understood at this time. There is evidence that the metabolic adjustment triggered by the absence of CAPN3 in muscle results in an aberrant regeneration; AMPK pathway activation has been shown to play an essential role. [53]

  • Dysregulation of Ca2+ metabolism has also been implicated to play an important role in the pathogenesis of LGMD2A. [54]

  • Biopsy pathology is typically dystrophic, sometimes characterized by frequent lobulated fibers.

  • Of patients with LGMD2A, 20%–30% exhibit normal CAPN3 protein levels as measured by Western blotting. [55]

  • On muscle biopsy, CAPN3 can be visualized by using Western blots but not muscle immunohistochemistry. Correlation between the degree of deficiency and the clinical phenotype can be total, partial, or (in rare cases) nonexistent. Expression of dystrophin and the sarcoglycans is normal. Expression of dysferlin can be reduced.

LGMD2B is caused by mutations on chromosome 2 in the dysferlin gene.

  • More than 300 mutations have been identified, most commonly missense, nonsense, small deletions, and splice-site mutations.

  • The type of mutation is not correlated with the phenotype, ie, LGMD versus Miyoshi distal myopathy. Both phenotypes have been described in the same family with identical mutations.

  • Dysferlin protein is a large membrane protein with sequence analogy to the nematode protein fer-1, and is a member of the ferlin family of proteins, which are all involved in calcium-dependent membrane fusion. Dysferlin protein has been localized to the sarcolemma, the T-tubule system, and cytoplasmic vacuoles. [56] Dysferlin is thought to be involved in the docking and fusion of intracellular vesicles to the sarcolemma during injury-induced membrane repair by interacting with other dysferlin molecules and other proteins. Some of these proteins include annexins A1 and A2 (phospholipid binding proteins), caveolin-3 (LGMD1C), calpain-3 (LGMD2A), the dihydropyridine receptor within the T-tubule system, and AHNAK (desmoyokin, a protein involved in cell membrane differentiation and repair). Dysfunction of dysferlin may lead to impaired muscle membrane repair as well as delayed myoblast fusion and maturation.

  • Ultrastructural studies have shown small sarcolemmal defects, replacement of the plasma membrane by multiple layers of vesicles, and small subsarcolemmal vacuoles, all suggesting that dysferlin is likely required for maintaining the structural integrity of the muscle fiber plasma membrane, and plasma membrane injury is an early event in the pathogenesis of dysferlinopathy.

LGMD2C–2F are caused by mutations in the sarcoglycan genes.

  • LGMD2C is caused by a mutation on chromosome 13 in the γ-sarcoglycan gene.

  • LGMD2D is caused by a mutation on chromosome 17 in the α-sarcoglycan (adhalin) gene.

  • LGMD2E is caused by a mutation on chromosome 4 in the β-sarcoglycan gene.

  • LGMD2F is caused by a mutation on chromosome 5 in the δ-sarcoglycan gene.

  • Missense and nonsense mutations are the most common for all the sarcoglycanopathies, though with γ-sarcoglycanopathies (LGMD2C), small or large deletions are also common.

  • Sarcoglycan protein complex is a transmembrane complex that is part of the large dystrophin glycoprotein complex. The core of the complex is made up of the β and δ subunits with weaker binding of the α and γ subunits. This complex likely does not bind directly to dystrophin, but binds to the dystroglycan complex which in turn binds to dystrophin. The sarcoglycan complex also binds strongly to sarcospan as well as to α-dystrobrevin and filamin.

  • The function of the sarcoglycan complex is unknown, but it likely stabilizes the dystrophin glycoprotein complex. In the absence of the sarcoglycan complex, binding of dystrophin to β-dystroglycan and binding of β-dystroglycan to α-dystroglycan are weakened.

  • The sarcoglycan complex may also play a role in cell signaling based on the following evidence. It may act as a receptor since it has cysteine bonds, common in other receptors, although no substrate has been identified. ATPase activity occurs in α-sarcoglycan. The sarcoglycan complex binds α-dystrobrevin, which in turn binds to syntrophin, which binds nNOS and voltage-gated sodium channels.

  • Muscle biopsy usually shows a dystrophic pattern of muscle-fiber necrosis and regeneration similar to that observed in Duchenne muscular dystrophy.

  • On immunohistochemistry, dystrophin staining is often slightly reduced, but may be normal (whereas sarcoglycan expression may be mildly reduced in Duchenne-Becker muscular dystrophy). α-sarcoglycan mutations cause absent or reduced α-sarcoglycan staining with preservation of staining for γ-sarcoglycan. Minimal or no staining occurs for β and δ-sarcoglycan. This is the only mutation for which the amount of residual staining (for α-sarcoglycan) and the clinical phenotype are correlated. β- and δ-sarcoglycan mutations usually cause absent staining of the entire sarcoglycan complex.

LGMD2G is caused by mutations on chromosome 17 in the telethonin gene.

  • Null mutations have been described in only a few families with a wide range of phenotypic variability.

  • Allelic with hereditary cardiomyopathy (CMD 1N & CMH25)

  • Telethonin protein (titin-cap protein) is a sarcomeric protein present in the Z disk that binds to titin and several other Z-disk proteins, and is thought to be important in sarcomere assembly. While LGMD2G patients with null mutations do not appear to have a primary defect in myofibril assembly, knock down of titin-cap protein results in decreased expression of several myogenic regulatory factors suggesting that titin-cap protein may function to permit signaling between the contractile apparatus and genes involved in muscle development or maintenance. [57]

  • Immunofluorescence and Western blot assays may show a telethonin deficiency. Full sequencing testing may be cost-effective in all cases, as the gene is composed only of two small exons.

LGMD2H is caused by mutations on chromosome 9 in TRIM32 (tripartite-motif containing gene 32).

  • Most patients have the D487N mutation. Different mutations in TRIM32 have also been found, but all mutations cluster in the NHL domain of TRIM32 protein.

  • Mutations in TRIM32 can also cause sarcotubular myopathy (see Congenital Myopathies) and Bardet-Biedl syndrome.

  • TRIM32 protein is an E3-ubiquitin ligase that transfers activated ubiquitin residues onto a target protein, tagging the protein for degradation in the proteosome.

  • All mutations in the NHL domain result in loss of the self-interacting ability of TRIM32 protein , as well as the loss of interaction of TRIM32 protein with E2N, a muscle-specific protein involved in the ubiquitination process . [19] While the disease mechanism is unknown, it is speculated that disruption in the ubiquitination process may lead to protein accumulation and subsequent cell stress and dysfunction.

  • On muscle biopsy, no protein accumulations or inclusions have been identified.

LGMD2I (MDDGC5) is caused by mutations on chromosome 19 in the FKRP gene.

  • Missense point mutations are the most common mutation. A homozygous Leu276Ileu mutation (826A>C) is particularly common and is present in about 90% of patients. The disease severity correlates with the mutation in the second allele; patients with a homozygous mutation are less severely affected. The most severe phenotype occurs when patients have compound heterozygous mutations for 2 other missense mutations or 1 missense and 1 nonsense mutation. This form is allelic with congenital muscular dystrophy 1C. (See Congenital Muscular Dystrophy.)

  • FKRP protein is a putative glycotransferase based on its sequence homology to fukutin. FKRP deficiency causes hypoglycosylation of α-dystroglycan, a component of the dystrophin-associated glycoprotein complex. α-dystroglycan hypoglycosylation is associated with loss of interaction with laminin α2, which in turn results in laminin α2 depletion. [58]

  • In muscle biopsy, antibodies to the glycosylated portion of α-dystroglycan show reduced staining (and decreased mass on Western blots). Antibodies to laminin-α2 may show reduced staining; however, in mild cases, this is often evident only on Western blots. No consistent relationship is noted  between clinical function and the degree of morphological pathology. 

LGMD2J is caused by mutations on chromosome 2 in the titin gene.

  • The most common mutation is an 11-base pair deletion-insertion mutation in the terminal exon. Finnish patients who are homozygous for this titin mutation develop autosomal recessive LGMD2J, while patients with a heterozygous mutation develop autosomal dominant Finnish (tibial) muscular dystrophy.

  • Titin protein is the largest protein found in humans. It is important for sarcomeric organization, stretch response, and sarcomerogenesis in myofibrils. It also likely plays a role in the assembly of contractile elements, regulation of the size of the Z disk, and in cell signaling pathways.

  • Titin binds caplain-3 in muscle, which may stabilize it from autolytic degradation. Muscle biopsy in patients with LGMD2J shows secondary deficiency of calpain-3. No signal is obtained using autoantibodies to the C-terminus region of titin near the common mutation site. This C-terminus region is important for calpain-3 binding and cell signaling pathways. Muscle biopsy in LGMD2J shows loss of calpain-3.

  • Allelic with hereditary cardiomyopathy syndromes (CMD 1G, CMH 9, EOMFC [early onset myopathy with fatal cardiomyopathy]).

LGMD2K (MDDGC1) is caused by mutations on chromosome 9 in the protein O-mannosyltransferase 1 (POMT1) gene.

  • LGMD2K is allelic with Walker-Warburg syndrome (see Congenital Muscular Dystrophy).

  • POMT1 protein is an O-mannosyltransferase that glycosylates α-dystroglycan and disease is likely related to reduced or abnormal glycosylation of α-dystroglycan. POMT enzymatic activity is inversely correlated with severity of clinical phenotype such that patients with a LGMD phenotype have mildly reduced activity and patients with a Walker-Warburg syndrome phenotype have severely reduced activity. [59]

  • Muscle biopsy shows decreased staining for α-dystroglycan.

LGMD2L is caused by a mutation on chromosome 11 in the ANO5 gene.

  • ANO5 encodes a member of the Anoctamin family, comprised of at least 10 proteins all with 8 transmembrane domains. The function of Anoctamin 5 is unknown, but other anoctamins have been recognized to code for calcium-activated chloride channels. [28]

  • The c.191dupA mutation may be a founder mutation, accounting for the high prevalence in families of northern European descent. [29]

  • In some biopsies in patients with Anoctamin 5 mutation, there is evidence of sarcolemmal membrane lesions and defective membrane repair. It is hypothesized that similar to mutations in dysferlin, mutations in anoctamin 5 may lead to LGMD due to defects in membrane repair.

LGMD2M (MDDGC4) is caused by mutations on chromosome 9 in the fukutin gene.

  • LGMD2M is allelic with Fukuyama congenital muscular dystrophy.

  • Fukutin is a putative glycosyltransferase and has sequence homologies to a bacterial glycosyltransferase, but its exact role and enzymatic substrate have not been determined. However, like other glycotransferases, disease is likely related to reduced or abnormal glycosylation of α-dystroglycan.

  • Muscle biopsy shows decreased staining for α-dystroglycan.

LGMD2N (MDDGC2) is caused by mutations on chromosome 14 in the POMT2 gene.

  • LGMD2N is allelic with Walker-Warburg syndrome (see Congenital Muscular Dystrophy).

  • POMT2 is an O-mannosyl transferase and is required to form a complex with POMT1 for enzyme activity. Similar to mutations in POMT1, disease is likely related to defective glycosylation of α-dystroglycan.

LGMD2O (MDDGC3) is caused by mutations on chromosome 1 in the POMGnT1 gene.

  • LGMD2O is allelic with muscle-eye-brain disease (see Congenital Muscular Dystrophy).

  • POMGnT1 is the glycosyltransferase O-mannose β-1,2-N-acetylglucosaminyl-transferase. It catalyzes the transfer of N -acetylglucosamine to the O-linked mannose of glycoproteins, including α-dystroglycan. Like other glycosyltransferase mutations disease is probably related to defective glycosylation of α-dystroglycan.

LGMD2P (MDDGC7) is caused by mutations on chromosome 3 in the DAG1 gene. [36]

  • DAG1 codes for α -dystroglycan, which is known to be modified by several glycotransfersases and mutations in several of these genes are causes of LGMD or congenital muscular dystrophy.

  • In these patients, there is a missense mutation in the DAG1 gene itself.

  • A mouse model of this mutation mimics the human disease. The mutation was shown to impair the receptor function of α -dystroglycan by inhibiting post-translational modification by LARGE disease (see Congenital Muscular Dystrophy).

LGMD2Q is caused by mutations on chromosome 8 in the plectin (PLEC1) gene. [37]

  • Plectin is present in muscle sarcolemma and is thought to be important as a linker of various cytoskeletal proteins, thereby maintaining cell integrity.

  • Eight plectin isoforms have been identified. In these families, there was a mutation in the initiation codon for isoform 1f. Plectin expression was reduced in muscle and there was almost no expression of plectin 1f mRNA.

  • Allelic with epidermolysis bullosa simplex syndromes (see Epidermolysis Bullosa). 

LGMD2R is caused by a mutation on chromosome 2 in the DES gene.

  • This disease is allelic LGMD1D and with myofibrillar myopathy 1 (see below).

  • Desmin is important in linking myofibrils to the sarcolemma, nucleus, and mitochondria.

  • In these patients, desmin staining in muscle was normal. [38] However, ultrastructural abnormalities typical for myofibrillar myopathies such as disruption of myofibrillar organization, formation of myofibrillar degradation products, and aggregation of membranous organelles were not present.

LGMD2S is caused by a mutation on chromosome 4 in the TRAPPC11 gene.

  • The TRAPP complex is involved in membrane trafficking.

  • Mutations impair the binding of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus. [39] There was delayed exit of proteins from the Golgi to the cell surface, and in particular alterations of the lysosomal glycoproteins lysosome-associated membrane protein1 (LAMP1) and LAMP2 support a defect in the transport of secretory proteins as a pathologic mechanism.

LGMD2T (MDDGA14) is caused by a mutation on chromosome 3 in the GMPPB gene.

  • LGMD2T is allelic with Walker-Warburg syndrome (see Congenital Muscular Dystrophy).
  • GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate [40, 41] . GDP-mannose is required for O-mannosylation of proteins and like other glycosyltransferase mutations disease is probably related to defective glycosylation of α-dystroglycan. 
  • Muscle biopsy of affected patients shows reduced glycosylation of α-dystroglycan.

LGMD2U (MDDGA7) is caused by a mutation on chromosome 7 in the ISPD gene

  • LGMD2U is allelic with Walker-Warburg syndrome (see  Congenital Muscular Dystrophy).
  • ISPD belongs to the glycosyltransferase-A family (as does LARGE) and is required for efficient O-mannosylation of alpha-dystroglycan. [42, 43]
  • Muscle biopsy of affected patietns shows reduced glycosylation of α-dystroglycan.

LGMD2V is caused by a mutation on chromosome 17 in the GAA gene (see Genetics of Glycogen-Storage Disease Type II (Pompe Disease) & Type II Glycogen Storage Disease (Pompe Disease)

  • LGMD2V is allelic with Late-onset Pompe disease (glycogen storage disease type 2)
  • α-1.4 glucosidase is a lysosomal enzyme that hydrolyzes α-1.4 linkages on carbohydrates.  A mutation causes glycogen accumulation in most tissues. 

LGMD2W is caused by a mutation on chromosome 2 in the LIMS2 gene

  • LIMS2 is a component of a complex that mediates multiple protein-protein interactions at adhesion sites between cells and the extracellular matrix and is critical for muscle attachment [60] . This complex also functions as a signaling mediator that transmits mechanical signals.
  • LIMS2 localizes to sarcomeric Z-disks and costameres in heart and skeletal muscle.
  • Patients have reduced staining for pinch2 (alternative name) at Z-disc.

LGMD2X is caused by a mutation on chromosome 6 in the POPDC1 (BVES) gene

  • POPDC1 belongs to a group of membrane proteins (popeye domain-containing proteins) that are abundantly expressed in skeletal muscle and heart [44] .  
  • These proteins bind cAMP and TREK1 (human potassium channel KCNK2) and may have regulatory roles in action potential generation.
  • In zebrafish, expression of the homologous mutation caused heart and skeletal muscle phenotypes that resembled those observed in patients.

Autosomal dominant LGMD

LGMD1A is caused by mutations on chromosome 5 in the myotilin gene.

  • Several different missense mutations have been identified.

  • The term myotilinopathy has been coined because of the overlapping features in patients described as having a LGMD or myofibrillar myopathy and a mutation in the myotilin gene. Furthermore, a large family described as having spheroid body myopathy (see Congenital Myopathies) was recently found to have a mutation in the myotilin gene.

  • Myotilin protein is associated with the Z disk and is expressed in skeletal muscle and, to a lesser extent, cardiac muscle. Myotilin protein binds to α-actinin, filamin C, and actin, and it is likely important in stabilizing and anchoring thin filaments to the Z disk during myofibrillogenesis.

  • Muscle biopsy shows muscle fiber degeneration/necrosis and nonhyaline or hyaline inclusions that stain positively for multiple proteins (a feature similar to that of other myofibrillar myopathies). Myotilin, dystrophin, neural-cell adhesion molecule (NCAM), desmin, plectin, gelsolin, ubiquitin, and prion protein all are found in the inclusions. Other consistent findings are rimmed or nonrimmed vacuoles, autophagic vacuoles, cytoplasmic or spheroid bodies, and mild evidence of denervation. On electron microscopy, there is Z-disk streaming and sarcomeric disruption.

LGMD1B is caused by mutations on chromosome 1 in the lamin A/C gene.

  • Missense and deletion mutations have been reported.

  • Mutations in lamin A/C can also cause Emery-Dreifuss muscular dystrophy, quadriceps myopathy, congenital muscular dystrophy with rigid spine, autosomal dominant dilated cardiomyopathy with AV block (or CMD1A, see the Neuromuscular Disease Center), Familial partial lipodystrophy (Köbberling-Dunnigan syndrome), Charcot-Marie Tooth type 2A, mandibuloacral dysplasia, and premature aging syndromes (Hutchinson-Gilford progeria, atypical Werner syndrome).

  • No clear genotype-phenotype correlation distinguishes the disorders listed above. Different phenotypes can occur in the same family. One individual can have more than 1 phenotype.

  • Lamin A/C is an intermediate filament in the inner nuclear membrane and nucleoplasm of almost all cells. Multiple functions are described, but the pathophysiologic basis for LGMD1B is unknown. Lamin A/C provides mechanical strength to the nucleus; helps to determine nuclear shape; anchors and spaces nuclear pore complexes; is essential for DNA replication and mRNA transcription; and binds to structural components (emerin, nesprin), chromatin components (histone), signal transduction molecules (protein kinase C), and several genetic regulatory molecules.

LGMD1C is caused by mutations on chromosome 3 in the caveolin-3 gene.

  • Most are autosomal dominant missense or deletion mutations in the scaffolding region, but a family with autosomal recessive disease has been described. The same mutation can cause different phenotypes (LGMD1C, elevated CK levels, rippling-muscle disease, distal myopathy, hypertrophic cardiomyopathy), even in the same family.

  • Caveolins are transmembrane proteins that are the principal component of caveolae. Caveolae are 30- to 60-nm invaginations in cell membranes that can bind several components of signal-transduction pathways and may act as a scaffold, placing members of the pathway in close proximity.

  • Caveolin-3 is a muscle-specific caveolin that is localized to the sarcolemma. It interacts with G proteins, a variety of signaling molecules, dystrophin, dystrophin associated proteins, phosphofructokinase, dysferlin, and nitric oxide synthase (nNOS).

  • All mutations in caveolin-3 decrease sarcolemmal immunostaining, suggesting that the mutation is due to a loss of function. A dominant negative effect has been noted in which an aberrant protein product forms aggregates that sequester the normal caveolin-3 in the Golgi apparatus. Other effects due to improper caveolin-3 oligomerization and membrane localization result in derangements of the T tubule system, alterations in the sarcolemmal membrane, and the formation of subsarcolemmal vesicles.

  • Muscle biopsy shows reduced or absent immunochemical staining for caveolin-3 at the sarcolemma, and this can be used as a screening test before searching for caveolin-3 mutations. In addition, immunochemical staining for dysferlin (caveolin-3 interactions) at the sarcolemma is reduced and the number of caveolae on electron microscopy is also reduced.

LGMD1D (note that some references call this LGMD1E) is caused by a mutation on chromosome 6 in the DES gene. [46] See below for myofibrillar myopathy MFM1.  

LGMD1E (note that some references call this LGMD1D) is caused by a mutation on chromosome 7 in the DNAJB6 gene (DNAJ/HSP40 Homolog, subfamily B, Member 6).

  • It is a member of the HSP40 family, a class of co-chaperones with a J domain. [47, 48] These co-chaperones interact with chaperones of the HSP70 family to protect client proteins from irreversible aggregation during protein synthesis or times of cellular stress.

  • Mutations have a dominant toxic effect, increasing the half-life of cytoplasmic isoform of DNAJB6 and reducing its protective antiaggregation effect.

  • It interacts with BAG3 (See below myofibrillar myopathy MFM6).

  • Muscle biopsy shows rimmed vacuolar myopathy. Aggregates contain DNAJB6, TDP-43, and SMI-31

LGMD1F is caused by a mutation on chromosome 7 in the transportin 3 (TNPO3) gene. [61]

  • Transportin 3 is a member of the importinb super-family that imports proteins into the nucleus, including serine/arginine-rich proteins that control mRNA splicing.

  • Muscle biopsy shows variable muscle fiber degeneration, desmin expression in muscle fibers, rimmed vacuoles, and abnormal nuclear morphology.

LGMD1G is caused by a mutation on chromosome 4 in the hetrogenous nuclear ribonucleoprotein D-like (HNRPDL) gene. [62]

  • HNPRDL is a member of the hetrogenous ribonucleoprotein family whose members participate in mRNA biogenesis and metabolism including the splicing of specific exons in pre-mRNA transcripts of muscle related genes.  .
  • Muslce biopsy shows muscle fiber necrosis, rimmed vacuoles and perimysial fibrosis.   

LGMD1H is caused by a mutation on chromosome 3 at the 3p25.1-p23 locus; the protein has not yet been identified.

LGMD1I is caused by in-frame deletion on c.643_663del21 in calpain-3 gene.

LGMDD5 is caused by mutations in α1, α2, or α3 subunits of collagen type VI. 

  • Allelic disorders include bethlem myopathy, myosclerosis, early-onset dystonia and Ullrich Scleroatonic muscular dystrophy

  • Collagen VI may play a role in anchoring basement menbranes and stabilizing cells in the extracellular matrix, via interactions with proteoglycans, integrins, and other proteins.

  • Mutations may result in lower protein level, misfolded protein, or defective assembly.

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