Dystrophin - an overview | ScienceDirect Topics (2023)

Dystrophin deficiency (Duchenne muscular dystrophy, Becker muscular dystrophy, and atypical forms)

Absence or deficiency ofdystrophinit is responsible for two disorders that cause progressive muscle destruction. The absence of dystrophin impairs the integrity of the sarcolemma membrane, making it susceptible to mechanical damage. Molecules such as calcium can gain access to the fiber, initiating a chain of destructive processes that lead to muscle fiber necrosis. Eventually, this process leads to severe muscle wasting and the replacement of muscle fibers with fibrous tissue.

The responsible gene is located on the short arm of the X chromosome at the Xp21 locus. The gene is extremely large, comprising more than 2.5 million base pairs and 79 exons, or coding regions. Approximately 65% ​​to 75% of cases are associated with a deletion or duplication of one or more exons in the gene. Genetic testing assays designed to detect deletions and duplications, such as multiplex ligation-dependent probe amplification (MLPA) and microarray-based comparative genomic hybridization (CGH) should first be used (Hegde MR et al., 2008;Sansovic et al., 2013). There are "hot spots" for these gene deletions, mainly between exons 43 and 52 and particularly 44 and 49 (Noble et al., 1997). The remaining 25% to 35% of cases are due to point mutations (many of which introduce a premature stop codon), minor deletions, or small insertions or duplications, best detected by next-generation sequencing. Whether an exclusion is inside or outside the frame (seechapter 48) determines if dystrophin is absentmuscle or present in a reduced altered form. This is of clinical importance because the former is usually associated with severe DMD, while the latter can cause a milder Becker variant (BMD). In BMD, the abnormal dystrophin retains enough function to slow the progression of the disease. The reading of the DNA code is trio by trio. Maintenance of this reading frame across the gene is necessary for dystrophin production. If a deletion removes a multiple of three base pairs, the reading frame may be intact upstream and downstream and may have limited meaning, as if the sentence "You can't eat the cat" were changed to "You can't eat the cat." cat". ". cat" and some modified dystrophin can be formed. This is often the situation in the mild form of dystrophin deficiency (BMD). In the severe form, the reading frame is destroyed, as if a deletion would result in the phrase "Yoc ann ote att hec at". There are exceptions to this rule, as frameshift deletions have been associated with the milder form of the disease, particularly at the 5' end of the gene in exons 3-7. The prevalence of DMD in the general population is approximately 3 per 100,000, and the incidence among male live births is 1 per 3,500. BMD is about one tenthso common Although inheritance is clearly X-linked recessive, almost a third of cases are sporadic. Presumably this is due to a spontaneous mutation that occurs in the child or in the mother's eggs.

Introduction

dystrophinit is a large 427 kDa cytoligand protein that connects the interior of the cell with the extracellular matrix. Although expressed in many tissues in the body, dystrophin has the critical function of stabilizing the muscle membrane (sarcolemma) during muscle contraction, and its absence results in Duchenne muscular dystrophy (DMD). Dystrophin's cytoligand function is primarily performed by two dystrophin domains. The N-terminal domain binds to filamentous actin within the cell, while the dystrophin- and cysteine-rich domain binds to β-dystroglycan embedded in the sarcolemma. β-dystroglycan further associates with α-dystroglycan which binds to the extracellular matrix and completes the transmembrane connection of intracellular actin to the extracellular matrix.blakeand another., 2002; Guiraudand another., 2015). Dystrophin and dystroglycans, as well as other integral membrane proteins such as sarcoglycans and sarcospan, form a complex known as the dystrophin glycoprotein complex (DGC).Extracted from Sonnemann, 2008). Dystrophin and DGC further associate with many additional proteins, such as microtubules, intermediate filaments, and neuronal nitric oxide synthase (nNOS), which allow dystrophin to have a broad influence on the cytoskeleton and signaling pathways.allenand another., 2016).

Dystrophin plays a critical role in muscle structure and function, and its absence results in DMD, a disabling and ultimately fatal disease. Most current clinical strategies, such as steroids and respiratory support, only improve disease pathology in the short term.Flanigan, 2014). Currently, there are 3 strategies to restore the dystrophin protein that have been successful in clinical trials: gene therapy, exon skipping, and stop codon reading (Shieh, 2018). However, in most cases, these therapeutic strategies do not completely recapitulate endogenous dystrophin, but instead restore dystrophin expression with small or large internal deletions. As highlighted in this review, recent studies are expanding our knowledge of the many binding partners of dystrophin and the functional significance of these interactions. Dystrophin therapeutic proteins with internal deletions are likely to compromise dystrophin function. In the effort to develop therapies to prevent or delay the fatality of DMD, there has never been a more critical time to consider what functions of dystrophin are essential for healthy muscle.

In this article, we review the domain structure of dystrophin, its interaction partners, truncated dystrophin isoforms, dystrophin-related diseases, and therapeutic strategies to restore or replace dystrophin.

Dystrophin glycoprotein complex (DGC).

dystrophinit is a structural protein that anchors the DGC to the cell membrane. DGC is a veritable constellation of polypeptides associated with a dozen genetically distinct muscular dystrophies (Figure 12-20). This complex serves several important functions. First, it is believed to be essential for maintaining the integrity of the muscle membrane by linking the actin cytoskeleton to the extracellular matrix. Second, it is necessary to position the proteins of the complex in the sarcolemma. Although the function of many of the proteins in the complex is unknown, their association with muscle disease indicates that they are essential components of the complex. Mutations in several of these proteins cause autosomal recessive muscular dystrophies and other congenital muscular dystrophies.Figure 12-20).

The fact that each component of CGD is affected by mutations that cause other types of muscular dystrophies underscores the principle that no protein functions in isolation, but rather is a component of a biological pathway or multiprotein complex. Mutations in genes encoding other components of a pathway or complex often lead to genocopies, as we saw earlier in the case of CF.

mechanical fragility of the membrane

dystrophinIt is a link between the intracellular cytoskeleton and the extracellular matrix. The carboxy terminus of dystrophin is attached to the sarcolemma, the surface membrane of striated muscle cells,^67–70binding to β-dystroglycan⁷¹and through it to other glycoproteins associated with dystrophin and α-dystroglycan, which binds the sarcolemma to the extracellular matrix.⁷²When dystrophin is not present, disconnection of β-dystroglycan contractile proteins results in loss of β- and α-dystroglycan and CGD from the sarcolemma. This disruption results in membrane embrittlement and abnormal permeability, particularly to calcium ions.

Duchenne muscular dystrophy and Becker muscular dystrophy

Duchenne muscular dystrophy (DMD) is the most common and severe type of muscular dystrophy, with an incidence of 1 per 3,500 male live births.²⁷⁷and a total male prevalence of about 50 to 60 × 10^–6.²⁷⁸Becker muscular dystrophy (MBD) is relatively rare, with an incidence of approximately 1 in18,000 male live births and a prevalence of 23.8 × 10^–6.²⁷⁸Both DMD and BMD are X-linked recessive diseases. The defect is located on the short arm of the X chromosome, in the Xp21 region, which contains the gene for the large protein Dp427, also known asdystrophin. The dystrophin gene is 2500 kilobases long with more than 70 exons.²⁷⁸Dystrophin is distributed not only in skeletal, cardiac, and smooth muscle, but also in the brain.²⁷⁹Due to the large size of the dystrophin gene, spontaneous new mutations are common, accounting for one third of new cases.²⁸⁰

The most common form of mutation is a deletion within the gene (65%-70% of DMD cases and >80% of MBD). Duplication and point mutations account for the rest. It also appears that there are "hot spots" in the first 20 exons and in the central region of the gene (exons 45-55) where deletions and duplications are likely to occur.²⁷⁸Female cases of DMD with 45,X and 46,XX karyotypes have been reported. The disease mechanism for the female 46,XX karyotype was thought to be preferential loss of the paternal X chromosome due to postzygotic nondisjunction and manifestation of the DMD gene from the maternal X chromosome in muscle cells.²⁸¹BMD is generally milder in severity than DMD because the disruption of the translation process occurs in the relatively distal part of the gene, leading to a reduced amount of truncated dystrophin protein.^278.282

Dystrophin, along with dystrophin-associated glycoproteins (DAGs), is involved in the stability of the sarcolemma. Dystrophin is responsible for maintaining the integrity of the muscle membrane, despite the fact that it represents only about 0.002% of the protein in skeletal muscle.²⁸³Dystrophin aggregates and binds to actin (at its N-terminus) and the DAG complex (at its C-terminus) to form a stable structure that interacts with laminin in the extracellular matrix.Figure 35.4). The lack or dysfunction of dystrophin leads to cell and membrane instability, with progressive leakage of intracellular components and elevation of creatine phosphokinase (CPK) levels. Eventually, the damaged muscle cell units are invaded by macrophages and destroyed. The current study suggests that cytotoxic T cells are likely to be to blame. Consequently, clinical muscular pseudohypertrophy occurs when layers of dead muscle are replaced by fibrofatty infiltrates. The loss of muscle units is responsible for weakness and contracture.²⁷⁹

dystrophin

dystrophinit is a 427 kilodalton protein that constitutes 0.01% of the total muscle protein and 5% of the proteins of the sarcolemma cytoskeleton. Dystrophin is located on the inside of the sarcolemma and is abundant at the myotendinous junction and at the postsynaptic membrane of the neuromuscular junction. Dystrophin forms an integral part of the cytoskeleton of a muscle and links the contractile apparatus to the sarcolemma. The N-terminus is the actin-binding domain, and the carboxy-terminal domain interacts with β-dystroglycan, as well as dystrobrevin and syntrophin. The central domain of the rod comprises most of the mass of the dystrophin molecule, forming a flexible rod-like structure. The fourth cysteine-rich domain also binds β-dystroglycan. The dystrophin-glycoprotein complex consists of numerous proteins, including dystroglycans (α and β), sarcoglycans (α, β, γ, δ, ε), sarcospan, syntrophin, and dystrobrevin. Peripheral members of the complex include neuronal nitric oxide synthase, caveolin, laminin, and merosin.

The DMD gene encoding the dystrophin protein is located on the short arm of the X chromosome, near the Xp21 region. The dystrophin gene is the largest gene identified to date, spanning more than 2.5 megabases (Mb) and containing at least 79 exons; the high rate of spontaneous mutation is a reflection of the large size of the gene. Dystrophin is expressed primarily in skeletal, cardiac, and smooth muscle cells, with smaller amounts expressed in the brain and retina. Dystrophin isoforms, which are smaller in size, are expressed in almost all tissues examined. Dystrophin in the brain is important in the maintenance of synapses; Deficiency of the brain dystrophin isoform is associated with the cognitive deficits seen in patients with dystrophin mutations. Deletions or abnormalities of the dystrophin gene cause an absence or deficiency of dystrophin, resulting in X-linked Duchenne and Becker muscular dystrophies.chapter 146).

dystrophin

dystrophinis a rod-shaped subsarcolemmal protein that stabilizes the sarcolemma by linking the actin cytoskeleton to the extracellular matrix via the dystrophin-associated glycoprotein complex.¹²⁵This connection protects muscle cells from contraction-induced damage.¹⁷⁹Enteroviruses are normally released from the cell by rupture of the cell membrane or by cell lysis.¹⁰⁷Consistent with these concepts, dystrophin deficiency has been shown in mice to predispose to cardiac cytopathic effects induced by Coxsackie virus and lead to increased virus replication in the hearts of dystrophin-deficient animals.¹¹³In addition, cell culture experiments showed that dystrophin expression protected against Coxsackie virus-mediated cell damage.¹¹³The markedly increased susceptibility of dystrophin-deficient mice to viral infection of the heart suggests that one of the mechanisms for increased cardiomyopathy in Duchenne muscular dystrophy is through increased susceptibility to viral infection of the heart. heart.

Dystrophin-associated proteins/glycoproteins

dystrophin

D DYSTROPHIN

dystrophinis a well-studied cytoskeletal protein that is most prominently expressed in skeletal and cardiac muscle.Hoffmannand another, 1987; Ahn and Kunkel, 1993). A large 400 kD protein, dystrophin is encoded by the Duchenne muscular dystrophy gene.Hoffman and Kunkel, 1989). Absent or greatly reduced dystrophin in muscle causes severe progressive skeletal damagemuscle weakness and may result in dilated cardiomyopathy. Lack of dystrophin expression also causes myopathy in mdx mice, a useful animal model for studying dystrophin function.

Dystrophin is found in both skeletal and cardiac muscle along the peripheral SL.francoand another, 1994; Arahataand another, 1988; Byersand another, 1991; Klietchand another, 1993), consistent with its role as part of a transsarcolemmal bridging structure. In skeletal muscle, most biochemical and immunocytochemical reports agree that dystrophin is not present in the T tubular portion of the SL. This difference in dystrophin distribution between peripheral SL and tubular T SL is consistent with previous studies demonstrating that in skeletal muscle the peripheral T and SL tubules have distinct ultrastructural features, contain several unique proteins, and appear to perform different functions at least relative to with E-C coupling. .

In summary, cytoskeletal proteins have many functions in cardiac muscle, including the structure of intracellular organelles, especially the sarcomeric units of the muscle; stabilize the SL at intercellular binding sites such as the intercalated disc or attach sarcomeres to the extracellular matrix in Z lines; and, most importantly, form cytoskeletal membrane junctions to integral membrane proteins. This binding of the cytoskeleton directly or through associated cytoskeletal proteins, such as ankyrin, can bind channels, exchangers, and receptors to form regional specializations within the membrane.