Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101578


Historical Background

Thirty years ago, the biochemical studies of plasma membranes of rodent NG108–15 neural hybrid cells, 14-day embryonic chicken brain, and mouse 3 T3 fibroblasts had led to the identification of cranin (LBP120), a glycosylated laminin-binding protein. Later, by sucrose-gradient centrifugation following purification of proteins from heavy microsomes of rabbit skeletal muscles using wheat germ agglutinin and DEAE-sepharose, four novel glycoproteins associated with dystrophin were purified and labelled as the “dystrophin-glycoprotein complex (DGC)” (Ervasti et al. 1990). At the center of this complex, the dystroglycan (DG) has been identified as a glycan component whose amino acid sequence is identical to cranin. Since then, other members of the DGC were identified. Thus, the DGC provides a link between proteins of the extracellular matrix (ECM) and the internal actin-cytoskeletal machinery (Fig. 1; Table 1). Also the cytoplasmic domain of DG interacts with several mediators of signaling pathways (Table 1; Fig. 4).
Dystroglycan, Fig. 1

Schematic representation of the dystroglycan and its main partners. The scheme brings together all the known partners of the DG in different types of tissues. O-mannosylated α-DG serves as binding partner for ECM proteins, such as laminins, perlecan, agrin, neurexin, pikachurin, slit, biglycan, and the causative organism of leprosy and arenaviruses. Laminins are major components of the basal lamina. Perlecan is a proteoglycan that binds and crosslinks ECM components. Agrin is a large proteoglycan of the neuromuscular junction. Neurexin is a presynaptic protein connecting neurons at the synapse. Pikachurin is localized to the synaptic cleft in the photoreceptor ribbon synapse. Slit is a chemorepellent protein, preventing the axon crossing of commissural neurons through the midline of the central nervous system. Biglycan is a leucine-rich proteoglycan found in a variety of ECM. Mycobacterium leprae and arenavirus are pathogens which cause leprosy and hemorrhagic fever respectively. The transmembrane and extracellular domains of β-DG interact with the sarcoglycan-sarcospan subcomplex. The cytoplasmic tail of β-DG binds the actin cytoskeleton via direct interaction with dystrophin/utrophin. Other intracellular molecules being a part of, or associated with, DGC are dystrobrevin, the syntrophin adapter proteins, and neural nitric oxide synthase (nNOS) (not drawn to scale)

Dystroglycan, Table 1

The dystroglycan and its associated partners



Binding sites

in ligands

Binding sites in DG



Laminin G-like modules

O-mannosylglycan protruding from the mucin-like region


Protein core of the COOH-terminal

third of α-DG

The protein core of the COOH-terminal third of α-dystroglycan


Laminin G modules

O-mannosylglycan protruding from the mucin-like region


Laminin G-like modules

O-mannosylglycan protruding from the mucin-like region


Laminin G-like modules

Mucin-like region


Laminin G-like modules

O-mannosylglycan protruding from the mucin-like region

Slit proteins

C-terminal domain

Mucin-like region

Mycobacterium leprae

Phenolic glycolipid-1 (PGL-1) and

21 kDa laminin-2-binding protein


O-mannosylglycan protruding from the mucin-like region



O-mannosylglycan protruding from the mucin-like region


WW domain

Phosphorylated Y in the C-terminal motif: PPxY892


WW domain

Nonphosphorylated Y in the C-terminal motif: PPxY892



The juxtamembrane portion of the cytoplasmic domain



The juxtamembrane portion of the cytoplasmic domain RKKRK




Cytoplasmic tail


SH3 domain

The C-terminal motif: PxxP

Myosin IIA


Cytoplasmic tail


N-term: Plakin domain. C-term: IF-binding domain

The C-terminal binding domain


IBB domain

The juxtamembrane portion of the cytoplasmic domain RKKRK



The juxtamembrane portion of the cytoplasmic domain: RKKRK

Src family kinases

WW domain

Phosphorylated Y in the C-terminal motif: PPxY892


SH3 domain

The C-terminal motif: PxxP

ERK extracellular signal-regulated kinase, Grb2 growth factor receptor-bound protein 2, IF intermediate filament

Gene, Protein Structure, Expression and Distribution

DG genes have been cloned and identified in a broad diversity of phyla. Analyses of the phylogenetic distribution of DG and its partners have identified that DG originated after the divergence of ctenophores from porifera and eumetazoa (see Table 2 in Adams and Brancaccio 2015).

Gene and Protein Structure

Using somatic cell hybrids and fluorescence in situ hybridization, the human gene (dystroglycan 1, DAG1) has been mapped to chromosome 3p21.1–21.31, the mouse gene to chromosome 9 in a region of conserved synteny with human 3p. The coding sequence is organized over a small and a large exon (2.4 kb) separated by a broad intron. The mature 5.8 kb transcript that contains an 895-residue open reading frame is translated in a protein with a molecular mass of 96 kD. Posttranslational modifications, including proteolysis, phosphorylation, and glycosylations, result in the mature form of DG (Fig. 2). The mature form is a type I transmembrane protein composed of two noncovalently interacting subunits: α-DG, an extracellular protein of 653 amino acids; and β-DG, a protein of 242 amino acids which contains extracellular, transmembrane, and cytoplasmic domains.
Dystroglycan, Fig. 2

Organization of the dystroglycan domains. Dystroglycan consists of two subunits, which are translated from a single mRNA as a propeptide. The first 29 amino acids represent a signal peptide (SP). Posttranslational processing through cleavage at Ser 654 yields the two noncovalently associated proteins α-DG and β-DG. The α-DG subunit contains two Ig-like domains, a domain similar to the S6 protein present in the small ribosomal subunit (S6-like domain) and a mucin-like domain that has a complex and still not fully characterized pattern of glycosylation. The β-DG exhibits an ectodomain that extends into the extracellular space with two cysteines (669 and 713) participating in disulfide bonds. It also exhibits a transmembrane domain (TM), a putative nuclear localization signal (NLS), and a cytoplasmic domain that contains three binding motifs for cytoplasmic proteins (see also Fig. 4)

The α-DG subunit possesses two globular domains flanking a central mucin domain that is characterized by a high concentration of proline residues and more than 40 serine/threonine residues. In the reticulum, in addition to proteolysis and N-glycosylation, the O-glycosylation on serine/threonine residues begins in the N-terminal half of the mucin domain leading to three types of O-mannosyl glycan structures (Endo 2015 for a review). In the endoplasmic reticulum, the glycosylation, that is shared among the three structures, starts by the addition of mannoses to hydroxyl groups on Ser/Thr residues by protein O-mannosyltransferase 1 and 2 (POMT-1, POMT-2). Then, the protein β-1,2-N-acetylglucosaminyltransferase (POMGnT1) transfers an N-acetylglucosamine residues to O-linked mannoses leading to the M1 glycan structure. A subset of M1 structures are modified by the N-acetylglucosaminyltransferase Vb (GnT-Vb, also referred to GnT-IX) that branches the mannose with a β1,6-linked N-acetyl glucosamine generating the M2 glycan structure. Subsequently, enzymes add galactose, fucose, glucuronic acid, neuraminic acid, and sulfate groups to M1 and M2 glycan structures in the Golgi apparatus. On a subset of mannoses, the glycosylation is extended to form an O-mannosyl trisaccharide leading to the M3 glycan structure (Fig. 3). Then possibly, a phosphorylation of mannoses allows the addition of xylosyl-glucuronyl polymers, named matriglycan, required to bind extracellular ligands (Fig. 3; Yoshida-Moriguchi and Campbell 2015). The glycosylation of α-DG is species specific, developmentally regulated, and tissue specific. It dictates the specificity of ligand binding. The extracellular ligands interact with α-DG in a Ca2+-dependent manner through laminin globular domains (LG modules), motifs of 177 amino acids in length presents in many ECM proteins (Fig. 1; Table 1).
Dystroglycan, Fig. 3

The steps of glycosylation pathways of the M3 glycan structure. The M3 glycan structure is synthesized in the endoplasmic reticulum. Protein O-mannosylation is initiated by POMT1/2 and extended by the protein O-linked mannose N-acetylglucosaminyltransferase 2 (POMGNT2) that adds an N-acetyl glucosamine (GlcNAc) to the mannose. The resulting disaccharide is modified by the β-1,3-N-acetylgalactosaminyltransferase 2 (β3GALNT2) that adds an N-acetyl galactosamine (GalNAc) to form the M3 structure, an O-mannosyl trisaccharide. If the 6-position of mannose is phosphorylated by protein-O-mannose kinase (SGK196, POMK), imperfectly known modifications of M3 glycan structures occur in the Golgi apparatus involving sequential enzymatic activities. The isoprenoid synthase domain-containing protein (ISPD), fukutin and fukutin-related protein (FKRP), sequentially act to transfer a tandem repeat of ribitol 5-phosphate (a phosphate ester of pentose alcohol) to the terminal GalNAc of M3 glycan structures (Gerin et al. 2016). Then, the transmembrane protein 5 (TMEM5), a xylose transferase, creates a linkage between a xylose and ribitol 5 phosphate. And then, the β1,4 glucuronyltransferase (β4GAT1) transfers a glucuronic acid residue onto the xylose. It thereby forms a glucuronyl-β1,4-xylosyl disaccharide. This disaccharide is required by the glycosyltransferase LARGE to catalyze the extension of a xylosyl–glucuronyl polysaccharide chains called matriglycan. These chains function as receptors for ECM ligands and their length correlates with the affinity of α-DG for its ligands (modified from Taniguchi-Ikeda et al. 2016; Praissman et al. 2016)

The β-DG has a single domain spanning the plasma membrane and an amino-terminal extracellular domain that binds to the carboxy-terminal globular domain of α-DG. The transmembrane domain of the β-DG interacts with sarcoglycans (α, β, γ, and δ), asparagine-linked glycosylated proteins containing a single transmembrane domain and with sarcospan that contains four transmembrane spanning domains with both N- and C-terminal regions located intracellularly. They form a subcomplex that stabilizes the α-DG association with β-DG at the cell surface. The cytoplasmic tail of β-DG interacts with signaling partners and with the proteins dystrophin, utrophin, syntrophins, and α-dystrobrevin, thereby to F-actin (Figs. 1 and 4).
Dystroglycan, Fig. 4

Schematic representation of the β-dystroglycan binding motifs for cytoplasmic proteins. The RKKRKGK site interacts with members of the ERM protein family (ezrin, radixin, and moesin), the Extracellular signal-related kinase-Mitogen-activated protein (ERK-MAP) kinase and importins. The LPPPETPN site is a potential site of interactions with actually unknown ligands. The RSPPPYVPP site interacts with various proteins depending on its phosphorylation. The nonphosphorylated tyrosine (Y892) allows the association of β-DG with the cytoskeletal adaptor proteins dystrophin/utrophin or proteins containing a SRC homology 3 domain (SH3 domain) as Grb2. Tyrosine phosphorylation of the PPxY recruits proteins with an SRC homology 2 domain (SH2 domain) (FYN, C-src tyrosine kinase, Src, NCK1, SHC1, Tks5, or Grb2). It also recruits Caveolin, an integral membrane protein which is the principal components of flask-shaped plasma membrane invaginations in muscle cells (not drawn to scale)

Dystroglycan Expression and Distribution

In humans, DG transcripts are detected in cells of the brain, kidney, liver, lung, diaphragm, placenta, pancreas, and stomach and with the most important level in cardiac and skeletal-muscle cells. In adult mice, Dg exhibits the same expression profile. In early mouse development, transcripts are first detected in cells around the Reichert’s membrane. Later during development, the protein is present within the plasma membranes of cells of the notochord, neural tube, myotomes, myocardium, spinal cord, lung buds, sex cords, mesonephric duct and tubules, and otic and optic vesicles. In Danio rerio, DG-maternal mRNAs are detected at the 128-cell stage and ubiquitously expressed throughout gastrulation. By the tailbud stage, transcripts are present in cells of the developing neural tube, throughout the paraxial mesoderm, in the notochord and hypochord. In Xenopus laevis, the DG-maternal mRNAs are detected from the four-cell stage. The protein is present on notochord cells and remains expressed throughout its differentiation process. It is also present on cells of the hypochord, brain, otic vesicles, eyes, visceral arches, somites, pronephros, skin, and heart. Several Drosophila melanogaster DG isoforms are generated via alternative splicing. Only one of these contains the full mucin-like domain. During oogenesis, DG is expressed in nurse, follicle, and female germline cells. During development, DG is detected in salivary gland, foregut, hindgut, brain primordium, peripheral nervous system, ventral nerve cord, longitudinal visceral muscle, tracheal system, heart, and aorta primordia. A high level of DG is detected on axons of photoreceptor cells in the optic stalk, lamina plexus, and medulla neuropil, and on glial cells of brain and optic lobes. In Caenorhabditis elegans, three genes encode three different isoforms of DG (dgn-1, dgn-2, and dgn-3). The dgn-1 gene is the most similar in sequence and structural organization to vertebrate. It encodes a protein that contains the N-terminal immunoglobulin-like domain and a reduced mucin-like domain. The protein lacks the proteolytic cleavage region and the residues involved in binding WW and SH3 domain-containing proteins. The dgn-2 and dgn-3 genes share only the α-DG C-terminus and the β-DG N-terminus domains with vertebrate. The dgn-1 is the unique nematode ortholog of vertebrate DG that is not expressed in muscle but expressed in gonads, epithelia, and neurons.

Intriguingly, the presence of β-DG in the nucleus of human carcinoma cells as well as in normal cell lines like mouse C2C12 myoblasts has been described.

Dystroglycan Functions

The analyses of the DG functions were mainly performed on various organisms, tissues, and cell cultures and based on knockout and specific knockout of DG, on inhibition of translation via morpholino antisense, on RNAi knockouts, and overexpression of DG or truncated forms of DG.

In mouse, the DAG1-null allele results in heterozygous animals that appear healthy and bred normally. However, the DG knockout is lethal for homozygous embryos that died at the embryonic day 6.5 because of the disorganization of Reichert’s membrane, the first extraembryonic basement membrane. The absence of DG causes a patchy distribution of laminins that precludes its assembly in the ECM and in addition embryos show gastrulation and mesoderm patterning defects. To overcome the embryonic lethality, chimeric mice were generated with embryonic stem cells targeted for both DAG1 alleles. Skeletal muscles differentiate normally but they develop a progressive muscular dystrophy characterized by centrally nucleated fibers, connective tissue infiltration, and significant differences in fiber size. At the sarcolemma, the entire DGC complex is disassembled, with dystrophin and sarcoglycans absent in fibers. The neuromuscular junctions are grossly disorganized and disrupted. The heart appears dilated because of an extensive connective tissue hyperplasia. In the kidney, different conditional knockout results in no aberrant phenotypes except an increase of the glomerular basement membrane thickness. In conditional DG knockouts in the cerebral cortex, the basal lamina of the glia limitans is severely disrupted leading to an overabundance of glia and the overextended migration of neurons in the developing brain. Also, the fissure between the hemispheres is lost. In peripheral nerves, selective absence of DG in Schwann cells causes structurally abnormal myelin sheaths around the neurons and throughout the internodal segments associated with a slow nerve conduction. Laminins are not deposited around the cells, and the sarcospan, sarcoglycan, and dystrobrevin are lost. Retinal photoreceptor-specific DG knockout inhibits pikachurin (a retinal ECM protein) accumulation on tips of photoreceptor synapses. In the neonatal brain of mouse, Dg regulates proliferation of neural stem and progenitor cells. It suppresses Notch activation in neural stem cells to promote the maturation of ependymal cells and the formation of stem cell niche. Additionally, it modulates oligodendrogenesis by regulating Notch activities to promote cell differentiation and myelination timely (McClenahan et al. 2016). All these findings point to the crucial role of DG during mouse development in the organization of the basement membranes, in the stability of the DGC, in the structural integrity of the sarcolemma, in the myelin integrity, in the node of Ranvier structure, in the formation of proper photoreceptor ribbon synaptic structures, and in oligodendrogenesis.

In Danio rerio, antisense morpholino oligonucleotide approach results in the destabilization of the embryonic muscles, with loss of sarcomere organization and necrosis of the developing muscle. The central nervous system and the neuromuscular junctions develop normally. A zebrafish mutant, designated patchytail, contains a point mutation resulting in a missense amino acid change of valine to aspartic acid within the Ig-like domain in the C-terminal region of α-DG. The muscle plasma membrane of patchytail fish appears disorganized and detached from the ECM. The mutant shows only subtle defects in cell organization in tectum and cerebellum and no significant neuromuscular junction defects. By contrast abnormal development of ganglion, lens and cornea layers in eyes are observed and the embryos do not survive more than ten day–post fertilization. On the other hand, in a mutation leading to a complete loss of DG, both myogenesis and myofibrillogenesis are unaffected while muscular dystrophy becomes apparent by 36 hours post fertilization, shortly after the elongation and fusion of myofibers. Therefore, in zebrafish, DG is dispensable for basement membrane formation during early development and for muscle formation while it is required for long-term survival of muscle cells.

The DG functions in Xenopus laevis development were analyzed using the morpholino knockout approach. It was shown that Dg is required for ECM organization, for somitogenesis, and for myoblast alignment during myogenesis. Also, the loss of DG precludes epithelial differentiation during the retinal, renal, and skin development. Interestingly, the Notch signaling pathway controls the transcription of DG during skin morphogenesis. Furthermore, point mutations in the Dg-cytoplasmic domain lead to the disruption of cell-mediolateral intercalation required for notochord formation and/or cytoskeleton integrity needed for vacuolation of notochord cells. Moreover, an overexpression of DG by microinjection of rabbit DG mRNA into embryos corrupts the aggregation of acetylcholine receptors and the structure of neuromuscular junctions.

In D. melanogaster, DG is required cell-autonomously to polarize both follicular epithelial cells and the oocyte. Mutations of protein O-mannosyl transferases, encoded by rotated abdomen (rt) or twisted (tw) genes, result in developmental failures of larval muscles, leading to defective muscles in adults characterized by a rotated abdomen phenotype. Genetic and RNAi-induced perturbations of DG specifically in mesoderm-derived tissues cause decreased cell mobility, age-dependent progressive deficits, and severe muscle degeneration in adult flies. DG depletion also leads to defective photoreceptor axon adhesion and migration during differentiation resulting in stunted photoreceptors in the adult. DG protein is present in ectodermal cells, but is absent in the ones that differentiate into tendon cells. These ones express miR-9a. Upon miR-9a deficiency, the DG is detected not only in muscle cells but also within the membrane of tendon cells leading to the alteration of muscle-tendon matrix assembly and disorganization of musculature assembly. Thus, DG is crucial for proper muscle-tendon attachments and its proper expression is adjusted by miR-9a (Yatsenkoet al. 2014). In the brain, the accuracy of neuronal proliferation, differentiation, and axon pathfinding depend on DG levels. It has been shown that the microRNA complex miR-310 s acts as an executive mechanism to buffer DG (Yatsenko et al. 2014).

In Caenorhabditis elegans, a deletion which removes a large coding region and partially the 3′ untranslated region of dgn-1 gene leads to viable but sterile worms. They show normal muscles and a severe disorganization of the somatic gonad epithelia, defects in vulval and excretory cell epithelialization, and impaired axon guidance of motoneurons.

In C2C12 myoblast cells, electron microscopy observation reveals β-DG localized in the inner nuclear membrane, the nucleoplasm, and nucleoli. Also, β-Dg interacts with nuclear envelope proteins emerin and lamins. This finding suggest that DG serves as a nuclear scaffolding protein involved in nuclear organization and nuclear envelope structure or that it interacts with transcriptionally active regions of the nucleus (Martínez-Vieyra et al. 2013).

All of this evidence, although conflicting in some areas, imply that DG is indispensable for normal development and is a vital contributor in maintaining cell and tissue integrity in adults.

Dystroglycan and Signaling Pathways

The C-terminal domain of β-DG is a short unfolded cytoplasmic tail that contains binding sites for numerous proteins at the juxtamembrane region and at the carboxy terminus (Figs. 2 and 4).

The juxtamembrane region of β-DG interacts with ezrin, and ERK-MAP kinase through a cluster of basic residues and possesses a nuclear localization signal. The interaction with ezrin, a member of the ERM protein family that crosslink actin filaments with plasma membranes, mediates actin cytoskeleton remodeling and induces peripheral filopodia and microvilli formation. These processes are controlled by complexes containing DG, ezrin, and members of the Dbl family of guanine nucleotide exchange factors. They are targeted to the membrane by DG and drive local activation of cell division cycle 42 protein (Cdc42), which in turn influences signaling events that initiate the formation of actin-rich surface protrusions. The juxtamembrane domain also interacts with protein kinases MEK and ERK, downstream components of the Extracellular signal-Regulated Kinase/Mitogen-Activated Protein Kinase (ERK-MAP) cascade. The link between β-DG and MEK is localized to membrane ruffles, while the link with ERK is found in focal adhesion in fibroblasts. Using the protein domain prediction program PSORT II, analysis unveils a putative nuclear localization signal (NLS) located in the cytoplasmic domain of β-DG within residues 776–782 (776RKKRKGK782) (Fig. 4). This putative NLS is totally conserved among the orthologous proteins of different species. It mediates the nuclear import of β-DG through a process dependent on importin α/β and Ran proteins. Interestingly, the NLS overlaps with the domain that interacts with ezrin suggesting a binding competition between importins and ezrin to regulate β-DG nuclear import. Instead it has been shown that cytoskeletal reorganization mediated by ezrin activation enhances the nuclear trafficking of β-DG through the importin nuclear import pathway (Vásquez-Limeta et al. 2014).

The carboxy terminus domain contains the PPxY motif, a motif governing interactions with proteins containing WW, SH2, and SH3 domains. DG-ECM interactions may phosphorylate tyrosine 892 in human and tyrosine 890 in mouse within the cytoplasmic domain of β-DG. The tyrosine kinase involved is the SH2 domain containing protein c-Src. Once tyrosine is phosphorylated, the β-Dg is no longer able to interact with proteins containing SH3 and WW domains leading to a loss of interaction with dystrophin/utrophin and thus with the cytoskeleton. Thus, the phosphorylation of tyrosine regulates β-DG cytoplasmic interactions, functioning as a balance between interaction with proteins containing SH3 or WW domains when it is not phosphorylated, and with proteins containing SH2 domain when it is phosphorylated (Fig. 4).

Other binding partners for β-DG include growth factor receptor-bound protein 2 (Grb2), caveolin, dynamin, and rapsyn. Grb2 is an adaptor protein composed of a single Src homology 2 domain (SH2) surrounded by two Src homology 3 domains (SH3) which permit Grb2 association with proteins containing tyrosine-phosphorylated residues and proline-rich regions, respectively. DG-Grb2 interaction may participate in the ERK-MAP kinase pathway involving MEK and ERK. The carboxy terminus of β-DG is associated with caveolin, a scaffolding protein and the main component of caveolae in muscle cells. The WW-like domain within caveolin directly recognizes the C-terminus PPxY motif. As the WW domain of dystrophin recognizes the same site, caveolin can block the interaction of dystrophin with β-DG suggesting that caveolin may competitively regulate the recruitment of dystrophin to the sarcolemma. Dynamin, a GTPase implicated in endocytosis, interacts directly with β-DG suggesting that this interaction regulates endocytosis in cells. The interaction with rapsyn, a Src-like kinase, leads to signaling events required for the formation of a specific complex essential for the agrin-mediated clustering of acetylcholine receptors at the neuromuscular junction.

Thus, DG and cytoplasmic proteins may be of biological importance in transducing signals arising from the binding of DG to ECM proteins. They contribute to regulate cytoskeletal assembly, cell shape, and intracellular signaling pathways.


The dystroglycanopathies forms a heterogeneous group of human rare diseases that have been classified as muscular dystrophy-dystroglycanopathy by Online Mendelian Inheritance in Man (OMIM), an Online Catalog of Human Genes and Genetic Disorders. They concern malformations during central nervous system and ocular development. These diseases are characterized by DG dysfunctions and classified into two groups. The primary dystroglycanopathies result from mutations in the DAG1 gene, the secondary dystroglycanopathies from the hypoglycosylation of α-DG.

Primary Dystroglycanopathies

The first case of primary dystroglycanopathy has been described in a Turkish woman with limb-girdle muscular dystrophy (LGMD) and severe mental retardation (Hara et al. 2011; OMIM #128239). It is caused by a homozygous missense mutation in DAG1 that generates a threonine-to-methionine substitution at amino acid residue 192. Using knock-in mice as model systems and in vitro binding assays, it has been shown that the mutation precludes activities of LARGE leading to defects in DG-laminin binding in skeletal muscle and brain. Another report describes a muscle-eye-brain (MEB) disease associated with an extended bilateral multicystic leucodystrophy in two Libyan siblings (Geis et al. 2013). This disease originates from a mutation identified in the extracellular domain of β-DG that substitutes a cysteine-to-phenylalanine at amino acid residue 669. It affects the highly conserved cysteine residue predicted to form a covalent intra-chain disulphide. The substitution changes the conformational structure of β-DG that disrupts its interaction with α-DG. Also, a homozygous loss-of-function mutation has been described in five female infants from a consanguineous Israeli-Arab family with intracranial calcifications associated with a Walker-Warburg syndrome (WWS, OMIM #236670) resulting in death soon after birth (Riemersma et al. 2015). A homozygous deletion, resulting in a frameshift and premature termination, causes this syndrome because a premature stop codon leads to the complete absence of both α- and β-DG.

Secondary Dystroglycanopathies

Secondary dystroglycanopathies are characterized by reduced glycosylation of DG generated by mutations in known or putative genes involved in the O-mannosyl-glycosylation of α-DG (Fig. 3; Yoshida-Moriguchi and Campbell 2015 for a complete list and references). The resulting defective glycosylation of α-DG impairs DG interactions with its extracellular partners, disrupting the link between the ECM and the cytoskeleton and also signaling pathways. These mutations are the underlying causes of a wide clinical spectrum including severe structural brain involvement resembling Walker–Warburg syndrome (WWS), muscle-eye-brain disease (MEB; OMIM #253280), Fukuyama congenital muscular dystrophy (FCMD; OMIM #253800), congenital muscular dystrophy types 1C and 1D (MDC1C; OMIM #606612; MDC1D; OMIM #608840), and some forms of autosomal recessive adult-onset limb-girdle muscular dystrophy (LGMD2I-2 N; OMIM #607155). Although the function of the isoprenoid synthase domain containing protein (ISPD; OMIM #614631) in mammals is not yet perfectly known, mutations in this protein have been found in nine patients from seven families who have phenotypes ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy (Cirak et al. 2013). Mutations of all these genes coding for proteins involved in the glycosylation pathways of α-DG are responsible for at least 50% of dystroglycanopathies suggesting that many of the secondary dystroglycanopathies remain unsolved and that additional mutations in genes await discovery.

Animal Models of Dystroglycanopathies

As DG is conserved in vertebrates and invertebrates, this offers a wide range of possible animal models to understand its role during embryogenesis, in different adult tissues and in pathogenesis of dystroglycanopathies. Thereby, several animal models including mouse, zebrafish, xenopus, drosophila, and worm have been generated. They are listed in Tables 1 and 2 in the review by Sciandra et al. 2015. Although dystroglycanopathies show various symptoms and anomalies, enzymatic corrections have been proposed based on studies using theses animal models. For example, this concerns antisense therapy for FCMD and gene therapy for FCMD, FKRP, and LARGE (Taniguchi-Ikeda et al. 2016 for a review).

Dystroglycan in Other Pathologies

In addition to the pathologies described above, DG is also involved in bacteria and virus infections and appears to be a suppressor of tumors.

DG is a cellular receptor for the causative organism of leprosy, Mycobacterium leprae, and for arenaviruses such as Lassa fever virus (LFV), African arenaviruses Mobala and Mopeia, and lymphocytic choriomeningitis virus (LCMV), which cause hemorrhagic fever. Schwann cells are targets for infection by Mycobacterium leprae, leading to the breakdown of the myelin sheath and consequently to neuronal and tissue death. Mycobacterium leprae interacts with α-DG on Schwann cells via the G domain of laminins that forms a bridge between bacteria and α-DG. The specificity of infection might be a result of Schwann-cell-specific glycosylation of α-DG. The arenaviruses bind to purified α-DG at a site mapped to the 18-amino acid domain spanning residues 316–334 of the mucin-like domain that overlaps with the ECM ligand-binding domain. Arenaviruses use α-DG for viral entry in a laminin-independent mechanism. The infection is due to competition between laminins and viruses for their shared binding site on α-DG leading to enhanced membrane fragility and instability (Oldstone and Campbell 2011). The attachment of viruses to DG induces tyrosine phosphorylation of β-DG at tyrosine 892 leading to the dissociation of DG from dystrophin/utrophin thereby facilitating the subsequent endocytosis of the virus-DG complex (Oppliger et al. 2016).

The role for DG in tumor metastasis was first demonstrated in prostate and breast cancers. Without describing here all data, it is known that mutations in DG are not yet described to be associated with cancer. While DG transcription appears largely unaltered in the majority of carcinomas, posttranscriptional mechanisms, including hypoglycosylation and proteolysis, are involved in the observed loss of DG function in cancer cell lines and primary tumors. They generate increased tumor aggressiveness, loss of extracellular matrix integrity and/or loss of intracellular signaling. For example, in adenocarcinoma, although α-DG is correctly expressed and trafficked to the cell surface, it is not functionally glycosylated caused by transcriptional silencing of LARGE. This abolishes DG ability to interact with ECM components leading to a failure of ECM-induced cell polarization thereby the invasiveness is promoted. Also, in adenocarcinoma cells, a cell density-dependent γ-secretase and furin, which could be Notch stimulated, lead to the degradation of β-DG in cytoplasmic fragments that are targeted and accumulated in the nucleus (Leocadio et al. 2016). Knowing that DG mediates transduction of signals, data point toward an effect on signal transduction pathways resulting in alterations of metabolism and growth rate in tumorigenic cells.


DG is a widely expressed transmembrane glycoprotein that requires complex and actually imperfectly known posttranslational processing to function as an ECM receptor. Synthesized as a single polypeptide, DG is cleaved to yield a cell-surface α-subunit and a transmembrane β-subunit. An extensive glycosylation of α-DG is required to function as a receptor for ECM proteins containing LG-domains. The phosphorylation of β-DG acts as a molecular switch to regulate DG interactions with various binding partners and different cellular adhesion and signaling functions. It also acts to determine its internalization by endocytosis and trafficking to the nucleus. Mutations of α, β-Dg or abnormalities in the posttranslational processing of α-DG disrupt its interactions with components of the ECM that result in human cancers and various congenital muscular dystrophies, referred as dystroglycanopathies. Phenotypic analyses, in both patients with dystroglycanopathies and animal models, show that DG is required in developmental and a variety of physiological processes: basement membrane assembly, muscle maintenance, peripheral-nerve myelination, neuromuscular-junction formation, neuronal migration in the brain, axon guidance, synapse formation and plasticity, and development of eye and brain. Also, DG serves as a cellular receptor for Old World arenaviruses, including the pathogenic Lassa fever virus. Interestingly, the requirements of DG for viral infections look like those for bindings to ECM proteins. In the future, a deeper understanding of both the molecular structure and cellular functions of DG, in particular in the nucleus, promises to realize the coming of new methods for treating viral infections and dystroglycanopathies.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Laboratoire de Biologie du développementSorbonne Universités, UPMC Universités Paris 06, CNRS, Institut de Biologie Paris Seine (LBD – IBPS)ParisFrance