Review
Muscular dystrophies involving the dystrophin–glycoprotein complex: an overview of current mouse models

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Abstract

The dystrophin–glycoprotein complex (DGC) is a multisubunit complex that connects the cytoskeleton of a muscle fiber to its surrounding extracellular matrix. Mutations in the DGC disrupt the complex and lead to muscular dystrophy. There are a few naturally occurring animal models of DGC-associated muscular dystrophy (e.g. the dystrophin-deficient mdx mouse, dystrophic golden retriever dog, HFMD cat and the δ-sarcoglycan-deficient BIO 14.6 cardiomyopathic hamster) that share common genetic protein abnormalities similar to those of the human disease. However, the naturally occurring animal models only partially resemble human disease. In addition, no naturally occurring mouse models associated with loss of other DGC components are available. This has encouraged the generation of genetically engineered mouse models for DGC-linked muscular dystrophy. Not only have analyses of these mice led to a significant improvement in our understanding of the pathogenetic mechanisms for the development of muscular dystrophy, but they will also be immensely valuable tools for the development of novel therapeutic approaches for these incapacitating diseases.

Introduction

Muscular dystrophy is a general term that describes a group of inherited and gradually debilitating myogenic disorders. Genetically, the pattern of inheritance can be X-linked recessive as in Duchenne or Becker muscular dystrophy (DMD/BMD), autosomal dominant as in limb–girdle muscular dystrophy type 1 (LGMD type 1), or autosomal recessive as in limb–girdle muscular dystrophy type 2 (LGMD type 2). DMD is the most common type of muscular dystrophy affecting approximately 1 out of 3500 males whereas the limb–girdle muscular dystrophies affect roughly 1 out of 20,000. Clinically, the muscular dystrophies are a heterogeneous group of disorders. Patients with DMD have a childhood onset phenotype and die by their early twenties as a result of either respiratory or cardiac failure, whereas patients with BMD have moderate weakness in adulthood and may have normal life spans. The limb–girdle muscular dystrophies have a highly variable onset and progression, but the unifying theme among the limb–girdle muscular dystrophies is the initial involvement of the shoulder and pelvic girdle muscles. Moreover, muscular dystrophies may or may not be associated with cardiomyopathy 1., 2., 3., 4..

Combined positional cloning and candidate gene approaches have been used to identify an increasing number of genes that are mutated in various forms of muscular dystrophy. According to the genetic basis, muscular dystrophies have now been reclassified and close to 30 genes have been implicated to cause muscular dystrophy (see [5] for review; see also Table 1). The first gene to be cloned was the dystrophin gene that is mutated in DMD and BMD [6]. Soon after the discovery of dystrophin, the dystrophin–glycoprotein complex (DGC) was identified and these studies opened up a new avenue of muscular dystrophy research 7., 8., 9.. Within the past couple of years, several targeted mouse models for DGC-associated muscular dystrophy have been generated and these mouse models, which are the focus of this review, have significantly contributed to understanding the pathogenetic mechanisms of muscular dystrophy.

Section snippets

Dystrophin–glycoprotein complex

The DGC is a large complex of membrane-associated proteins that is critical for the integrity of skeletal muscle fibers. This complex consists of dystrophin, the dystroglycans (α and β), the sarcoglycans (α, β, γ and δ), sarcospan, the syntrophins (α1, β1, β2; γ1- and γ2-syntrophins have been identified in neurons) and α-dystrobrevin 7., 8., 10., 11., 12., 13., 14., 15., 16., 17., 18., 19., 20., 21.. Dystrophin binds to cytoskeletal actin and to the transmembrane protein β-dystroglycan; the

Dystrophin

The mdx (X-chromosome-linked muscular dystrophy) mouse is the best-characterized mouse model for muscular dystrophy: >500 papers have been published in its analysis. As a result of a point mutation in exon 23 of the dystrophin gene, the mdx mouse is missing dystrophin [48]. Absence of dystrophin in skeletal muscle also affects the expression of the other DGC components at the sarcolemma [49]. Although this mouse has proved to be a valuable model for DMD, the progressive muscle-wasting disease

Animal models for dystroglycan deficiency

Dystroglycan was originally isolated from skeletal muscle but has since been shown to be expressed in a wide variety of tissues and is now considered to be the most broadly expressed DGC component 10., 81.. Besides muscle, dystroglycan is expressed at high levels in developing and adult tissues, typically in cell types that adjoin basement membranes such as epithelial and neural tissue 82., 83., 84.. Early in vitro work demonstrated a role for dys troglycan in epithelial morphogenesis [82]. In

Animal models for laminin-2 deficiency

In skeletal muscle, α-dystroglycan binds to the basement membrane protein laminin-2 (composed of laminin α2, β1 and γ1 chains) [24]. About 50% of the patients diagnosed with classical CMD show a primary deficiency of the laminin α2 chain and basement membrane perturbations [91]. Several mouse models for laminin-2 deficiency now exist, including the dy (dystrophia-muscularis) mouse, originally identified at the Jackson Laboratory 24., 92., 93., and an allelic mutant of the dy mouse, dy2J [94].

Animal models for integrin deficiency

Laminins also bind integrins, which are a large family of heterodimeric transmembrane cell surface receptors that function in a wide variety of cell interactions [98]. In skeletal muscle, the α7β1 integrin is the predominant integrin that binds laminin-2 [99]. It is possible that the functions of the DGC and the integrin α7 complex in skeletal muscle to some extent overlap. Mice lacking integrin α7 display a mild myopathy [100] and, interestingly, mice lacking both integrin α7 and dystrophin

Animal models for sarcoglycan–sarcospan deficiency

The sarcoglycan complex is a group of single-pass transmembrane proteins (α-, β-, γ- and δ-sarcoglycan) that is tightly associated with sarcospan to form a subcomplex within the DGC [105]. Although the exact function of the sarcoglycan–sarcospan complex is not known, it is well established that mutations in any of α-, β-, γ- and δ-sarcoglycan genes result in distinct forms of muscular dystrophy now collectively called sarcoglycanopathies 11., 14., 15., 16., 17., 18., 32.. A primary mutation in

Conclusions

Animal models lacking each component of the DGC have provided many new insights into the development of muscular dystrophy. Specifically, we have learned that muscular dystrophy can develop when DGC core components such as sarcoglycans, dystroglycan and dystrobrevins are missing from the skeletal muscle. In addition, muscular dystrophy can also develop when laminin-2 and integrins are absent. More importantly, analysis of these mouse models has unraveled novel pathogenetic mechanisms for the

Acknowledgments

We would like to thank all members of the Campbell laboratory for their critical reading of the manuscript and for fruitful discussions. Muscular Dystrophy Association supported this work. KP Campbell is an Investigator of the Howard Hughes Medical Institute.

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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