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1.  Functional Substitution by TAT-Utrophin in Dystrophin-Deficient Mice 
PLoS Medicine  2009;6(5):e1000083.
James Ervasti and colleagues show that injection of a truncated form of utrophin transduced all tissues examined, integrated with members of the dystrophin complex, and reduced serum levels of creatine kinase in a mouse model of muscular dystrophy.
The loss of dystrophin compromises muscle cell membrane stability and causes Duchenne muscular dystrophy and/or various forms of cardiomyopathy. Increased expression of the dystrophin homolog utrophin by gene delivery or pharmacologic up-regulation has been demonstrated to restore membrane integrity and improve the phenotype in the dystrophin-deficient mdx mouse. However, the lack of a viable therapy in humans predicates the need to explore alternative methods to combat dystrophin deficiency. We investigated whether systemic administration of recombinant full-length utrophin (Utr) or ΔR4-21 “micro” utrophin (μUtr) protein modified with the cell-penetrating TAT protein transduction domain could attenuate the phenotype of mdx mice.
Methods and Findings
Recombinant TAT-Utr and TAT-μUtr proteins were expressed using the baculovirus system and purified using FLAG-affinity chromatography. Age-matched mdx mice received six twice-weekly intraperitoneal injections of either recombinant protein or PBS. Three days after the final injection, mice were analyzed for several phenotypic parameters of dystrophin deficiency. Injected TAT-μUtr transduced all tissues examined, integrated with members of the dystrophin complex, reduced serum levels of creatine kinase (11,290±920 U versus 5,950±1,120 U; PBS versus TAT), the prevalence of muscle degeneration/regeneration (54%±5% versus 37%±4% of centrally nucleated fibers; PBS versus TAT), the susceptibility to eccentric contraction-induced force drop (72%±5% versus 40%±8% drop; PBS versus TAT), and increased specific force production (9.7±1.1 N/cm2 versus 12.8±0.9 N/cm2; PBS versus TAT).
These results are, to our knowledge, the first to establish the efficacy and feasibility of TAT-utrophin-based constructs as a novel direct protein-replacement therapy for the treatment of skeletal and cardiac muscle diseases caused by loss of dystrophin.
Editors' Summary
Muscular dystrophies are genetic (inherited) diseases in which the body's muscles gradually weaken and degenerate. The commonest and most severe muscular dystrophy—Duchenne muscular dystrophy—affects 1 in 3,500 boys (girls can be carriers of the disease but rarely have any symptoms). At birth, these boys seem normal but the symptoms of their disease begin to appear in early childhood. Affected children may initially have difficulty walking or find it to hard to sit or stand independently. As they age, their muscle strength progressively declines and most affected boys are confined to a wheelchair by the time they are 12 years old. The muscles involved in breathing also weaken and the heart muscle becomes enlarged. Few boys with Duchenne muscular dystrophy live beyond their early 20 s, usually dying from breathing or heart problems. At present there is no cure for Duchenne muscular dystrophy. However, physical therapy and treatment with steroids can prolong the ability of patients to walk, and assisted ventilation can help with their breathing.
Why Was This Study Done?
In all muscular dystrophies, one of the proteins needed to build and maintain healthy muscles is missing or nonfunctional because of a genetic change (mutation). In Duchenne muscular dystrophy the mutation is in dystrophin, a protein that is involved in the formation of the dystrophin–glycoprotein complex. This complex normally sits in the membranes that surround muscle fibers and protects these membranes from damage during muscle contraction. Consequently, in Duchenne muscular dystrophy, the muscle fiber membranes become damaged and eventually the muscle fibers die. Thus, if functional dystrophin could be introduced into the muscles of patients with Duchenne muscular dystrophy, it might be possible to reduce their symptoms and prolong their lives. Indeed, the effects of dystrophin deficiency in the dystrophin-deficient mdx mouse can be reduced by the introduction of an artificial gene that expresses dystrophin or the closely related protein utrophin. Unfortunately, this gene therapy approach has not yet been effectively demonstrated in humans. In this study, therefore, the researchers investigate whether utrophin protein can be introduced directly into dystrophin-deficient mouse muscles by exposing the muscle cells to utrophin fused to the protein transduction domain of the HIV-1 TAT protein. Most proteins will not cross cell membranes, but proteins fused to this cell-penetrating domain readily enter many cell types, including muscle cells.
What Did the Researchers Do and Find?
The researchers injected full-length utrophin fused to the TAT protein transduction domain (TAT-Utr) and a short, “micro” version of utrophin fused to the same domain (TAT-μUtr) into the abdomens of mdx mice and looked to see where the proteins ended up. After two injections, both proteins were present in a wide range of tissues and organs, including several types of muscle. However, the levels of TAT-Utr were much lower than those of TAT-μUtr. Next, the researchers injected another group of mdx mice with TAT-μUtr six times over three weeks. Again, TAT-μUtr was present in all the tissues that the researchers examined. Furthermore, μUtr–glycoprotein complexes formed in the TAT-μUtr injected mdx mice and the membrane integrity and overall health of the dystrophin-deficient muscles of the mdx mice improved compared to mdx mice treated with saline. Finally, the researchers report, TAT-μUtr injections greatly improved the contractile performance of the muscles of the mdx mice.
What Do These Findings Mean?
These findings provide the first demonstration that injection of TAT-utrophin protein fusions may provide a way to treat muscular dystrophies caused by the loss of dystrophin. However, although this direct protein-replacement therapy looks hopeful, approaches that work in animals do not necessarily work in people. In particular, for this approach to work in patients with muscular dystrophy, it would be necessary to give frequent, high-dose injections of the TAT-μUtr fusion protein, a process that could eventually trigger a deleterious immune response. Nevertheless, the researchers suggest that by combining this novel approach with other approaches that also increase utrophin expression, it might be possible to prevent or delay the development of the symptoms of Duchenne muscular dystrophy.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Institute of Neurological Disorders and Stroke provides information on muscular dystrophy and ongoing research into possible treatments (in English and Spanish)
The US National Human Genome Research Institute also provides basic information on Duchenne muscular dystrophy and links to additional resources
The UK National Health Service Choices Web site has pages for patients and caregivers on muscular dystrophy
The Nemours Foundation provides information about muscular dystrophy for parents, children, and teenagers
For links to further resources on muscular dystrophy, see also MedlinePlus
PMCID: PMC2680620  PMID: 19478831
2.  Ehlers-Danlos syndrome, clotting disorders and muscular dystrophy. 
Annals of the Rheumatic Diseases  1989;48(11):953-956.
Ehlers-Danlos syndrome includes 11 distinct entities. The diversity of this collagen dysplasia and its combination with other abnormalities make it difficult to understand physiopathologically. A case of Ehlers-Danlos syndrome is reported, which is novel owing to its combination with clotting abnormalities and especially with muscular dystrophy. To our knowledge this has not previously been reported. The patient was a young man aged 16 years who presented with Ehlers-Danlos syndrome satisfying Perelman's diagnostic criteria. His father and two brothers had comparable clinical symptoms, but his mother and sister were healthy. The four male subjects had an increased cephalin-kaolin time, reduced levels of factor VIII and Willebrand's factor (but without haemophilia A or Willebrand's disease), and, especially, an abnormal platelet ATP secretion. The proband alone had muscular disease with bilateral quadriceps fatigability and amyotrophy. The muscle enzyme levels were greatly increased, the electromyographic trace was myogenic, and the biopsy showed severe muscular dystrophy. This new observation poses the problem of the relation between clotting abnormalities and collagen abnormalities in the Ehlers-Danlos syndrome. It is difficult to classify this case within any of the 11 known types because of its muscular manifestations. It may perhaps be a fortuitous combination or an extension of the nosological framework of this syndrome.
PMCID: PMC1003920  PMID: 2512864
3.  Leaky ryanodine receptors in β-sarcoglycan deficient mice: a potential common defect in muscular dystrophy 
Skeletal Muscle  2012;2:9.
Disruption of the sarcolemma-associated dystrophin-glycoprotein complex underlies multiple forms of muscular dystrophy, including Duchenne muscular dystrophy and sarcoglycanopathies. A hallmark of these disorders is muscle weakness. In a murine model of Duchenne muscular dystrophy, mdx mice, cysteine-nitrosylation of the calcium release channel/ryanodine receptor type 1 (RyR1) on the skeletal muscle sarcoplasmic reticulum causes depletion of the stabilizing subunit calstabin1 (FKBP12) from the RyR1 macromolecular complex. This results in a sarcoplasmic reticular calcium leak via defective RyR1 channels. This pathological intracellular calcium leak contributes to reduced calcium release and decreased muscle force production. It is unknown whether RyR1 dysfunction occurs also in other muscular dystrophies.
To test this we used a murine model of Limb-Girdle muscular dystrophy, deficient in β-sarcoglycan (Sgcb−/−).
Skeletal muscle RyR1 from Sgcb−/− deficient mice were oxidized, nitrosylated, and depleted of the stabilizing subunit calstabin1, which was associated with increased open probability of the RyR1 channels. Sgcb−/− deficient mice exhibited decreased muscle specific force and calcium transients, and displayed reduced exercise capacity. Treating Sgcb−/− mice with the RyR stabilizing compound S107 improved muscle specific force, calcium transients, and exercise capacity. We have previously reported similar findings in mdx mice, a murine model of Duchenne muscular dystrophy.
Our data suggest that leaky RyR1 channels may underlie multiple forms of muscular dystrophy linked to mutations in genes encoding components of the dystrophin-glycoprotein complex. A common underlying abnormality in calcium handling indicates that pharmacological targeting of dysfunctional RyR1 could be a novel therapeutic approach to improve muscle function in Limb-Girdle and Duchenne muscular dystrophies.
PMCID: PMC3605002  PMID: 22640601
Muscular dystrophy; Ryanodine receptor; Calstabin1; Calcium
4.  Progress in gene therapy of dystrophic heart disease 
Gene therapy  2012;19(6):678-685.
The heart is frequently afflicted in muscular dystrophy. In severe cases, cardiac lesion may directly result in death. Over the years, pharmacological and/or surgical interventions have been the mainstay to alleviate cardiac symptoms in muscular dystrophy patients. Although these traditional modalities remain useful, the emerging field of gene therapy has now provided an unprecedented opportunity to transform our thinking/approach in the treatment of dystrophic heart disease. In fact, the premise is already in place for genetic correction. Gene mutations have been identified and animal models are available for several types of muscular dystrophy. Most importantly, innovative strategies have been developed to effectively deliver therapeutic genes to the heart. Dystrophin-deficient Duchenne cardiomyopathy is associated with Duchenne muscular dystrophy (DMD), the most common lethal muscular dystrophy. Considering its high incidence, there has been a considerable interest and significant input in the development of Duchenne cardiomyopathy gene therapy. Using Duchenne cardiomyopathy as an example, here we illustrate the struggles and successes experienced in the burgeoning field of dystrophic heart disease gene therapy. In light of abundant and highly promising data with the adeno-associated virus (AAV) vector, we have specially emphasized on AAV-mediated gene therapy. Besides DMD, we have also discussed gene therapy for treating cardiac diseases in other muscular dystrophies such as limb-girdle muscular dystrophy.
PMCID: PMC3628728  PMID: 22318092
muscular dystrophy; heart; cardiomyopathy; Duchenne muscular dystrophy; dystrophin; sarcoglycan
5.  Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage 
Recent studies have defined a group of muscular dystrophies, now termed the dystroglycanopathies, as novel disorders of glycosylation. These conditions include Walker–Warburg syndrome, muscle–eye–brain disease, Fukuyama-type congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, and limb-girdle muscular dystrophy type 2I. Although clinical findings can be highly variable, dystroglycanopathies are all characterized by cortical malformations and ocular defects at the more severe end of the clinical spectrum, in addition to muscular dystrophy. All of these disorders are defined by the underglycosylation of α-dystroglycan. Defective glycosylation of dystroglycan severs the link between this important cell adhesion molecule and the extracellular matrix, thereby contributing to cellular pathology. Recent experiments indicate that glycosylation might not only define forms of muscular dystrophy but also provide an avenue to the development of therapies for these disorders.
PMCID: PMC2855642  PMID: 16932553
dystroglycan; glycosylation; laminin; lissencephaly; neuromuscular junction; skeletal muscle
6.  Specific Loss of Histone H3 Lysine 9 Trimethylation and HP1γ/Cohesin Binding at D4Z4 Repeats Is Associated with Facioscapulohumeral Dystrophy (FSHD) 
PLoS Genetics  2009;5(7):e1000559.
Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscular dystrophy in which no mutation of pathogenic gene(s) has been identified. Instead, the disease is, in most cases, genetically linked to a contraction in the number of 3.3 kb D4Z4 repeats on chromosome 4q. How contraction of the 4qter D4Z4 repeats causes muscular dystrophy is not understood. In addition, a smaller group of FSHD cases are not associated with D4Z4 repeat contraction (termed “phenotypic” FSHD), and their etiology remains undefined. We carried out chromatin immunoprecipitation analysis using D4Z4–specific PCR primers to examine the D4Z4 chromatin structure in normal and patient cells as well as in small interfering RNA (siRNA)–treated cells. We found that SUV39H1–mediated H3K9 trimethylation at D4Z4 seen in normal cells is lost in FSHD. Furthermore, the loss of this histone modification occurs not only at the contracted 4q D4Z4 allele, but also at the genetically intact D4Z4 alleles on both chromosomes 4q and 10q, providing the first evidence that the genetic change (contraction) of one 4qD4Z4 allele spreads its effect to other genomic regions. Importantly, this epigenetic change was also observed in the phenotypic FSHD cases with no D4Z4 contraction, but not in other types of muscular dystrophies tested. We found that HP1γ and cohesin are co-recruited to D4Z4 in an H3K9me3–dependent and cell type–specific manner, which is disrupted in FSHD. The results indicate that cohesin plays an active role in HP1 recruitment and is involved in cell type–specific D4Z4 chromatin regulation. Taken together, we identified the loss of both histone H3K9 trimethylation and HP1γ/cohesin binding at D4Z4 to be a faithful marker for the FSHD phenotype. Based on these results, we propose a new model in which the epigenetic change initiated at 4q D4Z4 spreads its effect to other genomic regions, which compromises muscle-specific gene regulation leading to FSHD pathogenesis.
Author Summary
Most cases of facioscapulohumeral muscular dystrophy (FSHD) are associated with a decrease in the number of D4Z4 repeat sequences on chromosome 4q. How this leads to the disease remains unclear. Furthermore, D4Z4 shortening is not seen in a small number of FSHD cases, and the etiology is unknown. In the cell, the DNA, which encodes genetic information, is wrapped around abundant nuclear proteins called histones to form a “beads on a string”–like structure termed chromatin. It became apparent that these histones are modified to regulate both maintenance and expression of genetic information. In the current study, we characterized the chromatin structure of the D4Z4 region in normal and FSHD patient cells. We discovered that one particular histone modification (trimethylation of histone H3 at lysine 9) in the D4Z4 repeat region is specifically lost in FSHD. We identified the enzyme responsible for this modification and the specific factors whose binding to D4Z4 is dependent on this modification. Importantly, these chromatin changes were observed in both types of FSHD, but not in other muscular dystrophies. Thus, this chromatin abnormality at D4Z4 unifies the two types of FSHD, which not only serves as a novel diagnostic marker, but also provides new insight into the role of chromatin in FSHD pathogenesis.
PMCID: PMC2700282  PMID: 19593370
7.  Vladimir Karlovich Roth (1848-1916): the founder of neuromuscular diseases studies in Russia 
Acta Myologica  2014;33(1):34-42.
This article shortly examines the biography, scientific activity and scientific work on neuromuscular diseases of the famous Russian neurologist Vladimir Roth who was the founder of neuromuscular disorders study in Russia. In 1876 he was the first in Russia who performed an autopsy and a detailed histological study of a case of progressive muscular atrophy, in which he did not find changes in the nervous system. He called this disease "muscular tabes" i.e. myopathy. In 1884 Vladimir Roth expressed his opinion about the nosological place of the peripheral type of muscular tabes to be considered as a distal myopathy. Dr. Roth became well-known for his monograph of the neuromuscular diseases, published in Moscow in 1895 under the name "Muscular Tabes" in which he described the history of neuromuscular diseases in a very detailed way, analyzing 1014 cases published in the world literature from 1830 to 1893 and 125 personal observations in the period 1874-1894. He performed a thorough analysis of the pattern of muscle involvement using both electrodiagnostic and histological study of muscles and central/peripheral nervous system. We report a short review of this monograph and two cases of peripheral (distal) myopathy.
PMCID: PMC4021629  PMID: 24843233
Muscular tabes; distal myopathy; peripheral neuromuscular involvement
8.  Continuous Infusion Propofol General Anesthesia for Dental Treatment in Patients With Progressive Muscular Dystrophy 
Anesthesia Progress  2005;52(1):12-16.
Progressive muscular dystrophy may produce abnormal reactions to several drugs. There is no consensus of opinion regarding the continuous infusion of propofol in patients with progressive muscular dystrophy. We successfully treated 2 patients with progressive muscular dystrophy who were anesthetized with a continuous infusion of propofol. In case 1, a 19-year-old, 59-kg man with Becker muscular dystrophy and mental retardation was scheduled for dental treatment under general anesthesia. General anesthesia was maintained by a continuous infusion of 6–10 mg/kg propofol per hour and an inhalational mixture of 67% nitrous oxide and 33% oxygen. No complications were observed during or after the operation. In case 2, a 5-year-old, 11-kg boy with Fukuyama type congenital muscular dystrophy and slight mental retardation was scheduled for dental treatment under general anesthesia. General anesthesia was maintained with a continuous infusion of 6–12 mg/kg propofol per hour and an inhalational mixture of 0.5–1.5% sevoflurane in 67% nitrous oxide and 33% oxygen. No complications were observed during or after the operation. It is speculated that a continuous infusion of propofol in progressive muscular dystrophy does not cause malignant hyperthermia because serum levels of creatine phosphokinase and myoglobin decreased after our anesthetic management. Furthermore, our observations suggest that sevoflurane may have some advantages in patients with progressive type muscular dystrophies other than Duchenne muscular dystrophy and Becker muscular dystrophy. In conclusion, our cases suggest that a continuous infusion of propofol for the patients with progressive muscular dystrophy is a safe component of our anesthetic strategy.
PMCID: PMC2526213  PMID: 15859443
Propofol; Progressive muscular dystrophy; General anesthesia; Sevoflurane
9.  Distinction between Duchenne and other muscular dystrophies by ribosomal protein synthesis. 
Journal of Medical Genetics  1975;12(1):49-54.
Ribosome concentration, ribosome distribution on sucrose density gradients, and in-vitro ribosomal amino-acid incorporation (noncollagen and collagen synthesis) were studied in muscle biopsy samples obtained from 30 patients with Duchenne muscular dystrophy, seven patients with Becker muscular dystrophy, and 10 with facioscapulohumeral muscular dystrophy. Ribosome concentration was normal in Duchenne and facioscapulohumeral and decreased in Becker muscular dystrophy. Distribution of ribosomes in sucrose density gradients showed abnormalities (sharp monosomal peak and fewer polyribosomes) only in Duchenne muscular dystrophy and was normal in the other two types. In-vitro amino-acid incorporation of ribosomes in Duchenne muscular dystrophy revealed high collagen and low noncollagen synthesis of the heavy polyribosomes. This abnormality is controlled by an undetermined enzymatic factor belonging to the soluble enzyme fraction. Supplementation of the dystrophic heavy polyribosomes with normal soluble enzymes restored the synthesis of collagen to that of the controls. Heavy polyribosomes extracted from normals or from carriers produce proportionately more collagen in the presence of soluble enzyme fraction from Duchenne muscular dystrophy than in the presence of their homologous enzymes. In Becker muscular dystrophy, both noncollagen and collagen synthesis of the heavy polyribosomes were increased, under the influence of ribosomal factors. The different protein synthesis in Duchenne and Becker muscular dystrophies suggests that these conditions are non-allelic. In facioscapulohumeral muscular dystrophy the changes in protein synthesis occurred only in the early stage of the disease and consisted of increased noncollagen synthesis of the light polyribosomes, while the heavy polyribosomes had normal activity including collagen synthesis. This reaction was controlled by ribosomal factors.
PMCID: PMC1013230  PMID: 164552
10.  Zebrafish models for human FKRP muscular dystrophies 
Human Molecular Genetics  2009;19(4):623-633.
Various muscular dystrophies are associated with the defective glycosylation of α-dystroglycan and are known to result from mutations in genes encoding glycosyltransferases. Fukutin-related protein (FKRP) was identified as a homolog of fukutin, the defective protein in Fukuyama-type congenital muscular dystrophy (FCMD), that is thought to function as a glycosyltransferase. Mutations in FKRP have been linked to a variety of phenotypes including Walker–Warburg syndrome (WWS), limb girdle muscular dystrophy (LGMD) 2I and congenital muscular dystrophy 1C (MDC1C). Zebrafish are a useful animal model to reveal the mechanism of these diseases caused by mutations in FKRP gene. Downregulating FKRP expression in zebrafish by two different morpholinos resulted in embryos which had developmental defects similar to those observed in human muscular dystrophies associated with mutations in FKRP. The FKRP morphants showed phenotypes involving alterations in somitic structure and muscle fiber organization, as well as defects in developing eye morphology. Additionally, they were found to have a reduction in α-dystroglycan glycosylation and a shortened myofiber length. Moreover, co-injection of fish or human FKRP mRNA along with the morpholino restored normal development, α-dystroglycan glycosylation and laminin binding activity of α-dystroglycan in the morphants. Co-injection of the human FKRP mRNA containing causative mutations found in human patients of WWS, MDC1C and LGMD2I could not restore their phenotypes significantly. Interestingly, these morphant fish having human FKRP mutations showed a wide phenotypic range similar to that seen in humans.
PMCID: PMC2807370  PMID: 19955119
11.  Limb-girdle muscular dystrophy subtypes: First-reported cohort from northeastern China 
Neural Regeneration Research  2013;8(20):1907-1918.
The relative frequencies of different subtypes of limb-girdle muscular dystrophies vary widely among different populations. We estimated the percentage of limb-girdle muscular dystrophy subtypes in Chinese people based on 68 patients with limb-girdle muscular dystrophy from the Myology Clinic, Neurology Department, First Hospital of Jilin University, China. A diagnosis of calpainopathy was made in 12 cases (17%), and dysferlin deficiency in 10 cases (15%). Two biopsies revealed α-sarcoglycan deficiency (3%), and two others revealed a lack of caveolin-3 (3%). A diagnosis of unclassified limb-girdle muscular dystrophy was made in the remaining patients (62%). The appearances of calpain 3- and dysferlin-deficient biopsies were similar, though rimmed vacuoles were unique to dysferlinopathy, while inflammatory infiltrates were present in both these limb-girdle muscular dystrophy type 2D biopsies. Macrophages were detected in seven dysferlinopathy biopsies. The results of this study suggest that the distribution of limb-girdle muscular dystrophy subtypes in the Han Chinese population is similar to that reported in the West. The less necrotic, regenerating and inflammatory appearance of limb-girdle muscular dystrophy type 2A, but with more lobulated fibers, supports the idea that calpainopathy is a less active, but more chronic disease than dysferlinopathy. Unusual features indicated an extended limb-girdle muscular dystrophy disease spectrum. The use of acid phosphatase stain should be considered in suspected dysferlinopathies. To the best of our knowledge, this is the first report to define the relative proportions of the various forms of limb-girdle muscular dystrophy in China, based on protein testing.
PMCID: PMC4145977  PMID: 25206500
neural regeneration; limb-girdle muscular dystrophy; calpain 3; α-sarcoglycan; dysferlin; caveolin-3; grants-supported paper; neuroregeneration
12.  A Structure of a Collagen VI VWA Domain Displays N and C Termini at Opposite Sides of the Protein 
Structure(London, England:1993)  2014;22(2):199-208.
Von Willebrand factor A (VWA) domains are versatile protein interaction domains with N and C termini in close proximity placing spatial constraints on overall protein structure. The 1.2 Å crystal structures of a collagen VI VWA domain and a disease-causing point mutant show C-terminal extensions that place the N and C termini at opposite ends. This allows a “beads-on-a-string” arrangement of multiple VWA domains as observed for ten N-terminal domains of the collagen VI α3 chain. The extension is linked to the core domain by a salt bridge and two hydrophobic patches. Comparison of the wild-type and a muscular dystrophy-associated mutant structure identifies a potential perturbation of a protein interaction interface and indeed, the secretion of mutant collagen VI tetramers is affected. Homology modeling is used to locate a number of disease-associated mutations and analyze their structural impact, which will allow mechanistic analysis of collagen-VI-associated muscular dystrophy phenotypes.
•The structure of a VWA domain (N5) of collagen VI at 1.2 Å is presented•N and C termini of the domain are at opposite ends•The structure with a myopathy-causing mutation shows altered interaction interface•The impact of mutations in collagen VI VWA domains was analyzed
Becker et al. describe a crystal structure of a von Willebrand factor A (VWA) domain, which has a C-terminal extension that places the N- and C-termini at opposite ends not seen before for A domains. This allows a “beads-on-a-string” arrangement of multiple VWA domains as observed for the collagen VI α3 chain.
PMCID: PMC3919171  PMID: 24332716
13.  Characteristics of neurons and glia in the brain of Fukuyama type congenital muscular dystrophy 
Acta Myologica  2008;27(1):9-13.
Fukuyama type congenital muscular dystrophy accompanies central nervous system and ocular lesions. Morphological findings suggest that major central nervous system lesions, such as cortical dysplasia, are caused by the abnormal glia limitans due to an impairment of astrocytes. Increase of corpora amylacea and neurofibrillary tangles suggests acceleration of the aging process in the Fukuyama type congenital muscular dystrophy brain. Glycosylation of α-dystroglycan is decreased in the central nervous system of Fukuyama type congenital muscular dystrophy in a similar manner to the skeletal muscle, but dystroglycan mRNA levels appear to be increased. Glycosylated α-dystroglycan is reduced in the glia limitans formed by astrocytic endfeet. Slight accumulation of Nε-(carboxymethyl)lysine, an oxidative modification product, is observed in astrocytes of Fukuyama type congenital muscular dystrophy and in an astrocytoma cell line with suppressed fukutin expression. Cerebral cortical neurons of Fukuyama type congenital muscular dystrophy and controls react with an antibody for core α-dystroglycan but not with an antibody for glycosylated α-dystroglycan. Carboxymethyl lysine is accumulated in cortical neurons of a severe case of Fukuyama type congenital muscular dystrophy. Both astrocytes and neurons appear to be sensitive to oxidative stress when fukutin is suppressed. However, it is still unclear how the loss of fukutin causes astrocytic and neuronal dysfunction. Since the central nervous system is composed of several components that are closely related to each other, more investigations are needed for thorough understanding of the Fukuyama type congenital muscular dystrophy brain. Moreover, since astrocytes and epithelial cells may show different cellular responses to fukutin suppression, it seems important to evaluate the functions of fukutin in each type of cell or tissue, not only to prove the pathogenesis of Fukuyama type congenital muscular dystrophy, but also for applying appropriate therapies, especially those at molecular level.
PMCID: PMC2859607  PMID: 19108571
Fukuyama type congenital muscular dystrophy (FCMD); neuron; glia
14.  Possible neurogenic factor in muscular dystrophy: its similarity to denervation atrophy1 
Muscle biopsy specimens from 179 cases of muscular dystrophies and from 140 cases of anterior horn cell disorders (from a total of 1,348 biopsied patients) were examined histologically. There were 72 cases of Duchenne type muscular dystrophy (DMD), five of Becker type MD, four girls with myopathy resembling DMD, 40 with limb-girdle, 10 with facioscapulohumeral, seven with late onset, 13 with congenital, and 28 with unclassifiable muscular dystrophies. Groups of small atrophied muscle fibres were encountered in 42 (23%) of the cases in this group, most frequently in patients with limb-girdle, facioscapulohumeral, and least frequently with DM dystrophy. In the second group there were 25 cases of infantile, 38 of juvenile, and 39 of adult spinal muscular atrophy (SMA); there were 21 patients with motor neurone disease (MND), six with poliomyelitis, and 11 with an unclassifiable type of anterior horn cell disorder. Pseudomyopathic changes were encountered in 43 (30%) of all cases in this group. They were most frequently present among patients with juvenile and adult SMA and in those with MND. The presence of group atrophy in muscular dystrophy is considered significant myopathological evidence of a denervation process. On the other hand, pseudomyopathic changes, variation in fibre size, rounding, central nuclei, and increase in connective tissue occurring in various anterior horn cell disorders are seen not to be specific `myopathic' changes. Thus there was an overlap of pathological reactions in muscles from the dystrophies and the neurogenic atrophies. Comparably atrophied fibres (much less than 2 SDs below the normal mean diameter) and hypertrophied fibres (much more than 2 SDs above the normal mean diameter) were encountered in both dystrophy and neurogenic atrophy, considering the large muscles of the limb. Likewise, the mean fibre diameters were comparable in DMD and in juvenile SMA. The fourth evidence of a neurogenic factor in muscular dystrophy was derived from an examination of SDH preparations of muscle. There was a preponderance of type I muscle fibres in dystrophic muscles compared with specimens from controls, suggesting depletion of type II fibres. It appears that the concept of muscular dystrophy as a primary muscle disease needs to be re-examined.
PMCID: PMC494339  PMID: 4714102
15.  Linkage between the loci for benign (Becker-type) X-borne muscular dystrophy and deutan colour blindness 
Journal of Medical Genetics  1974;11(4):317-320.
A family is described in which benign Becker type X-linked muscular dystrophy and deutan colour blindness are segregating. The lod scores from this family have been added to those obtained in a family previously reported (Emery, 1968/1969) and give an estimate of 0·23 for the recombination fraction with 95% confidence limits of 0·13 to 0·43. These results confirm the linkage relationships between deutan colour blindness and Becker muscular dystrophy but since the loci for Duchenne muscular dystrophy and colour blindness are not within measurable distance of each other these results indicate that the Becker and Duchenne types of X-linked muscular dystrophy are not allelic.
PMCID: PMC1013197  PMID: 4548442
16.  Modulation of Myoblast Fusion by Caveolin-3 in Dystrophic Skeletal Muscle Cells: Implications for Duchenne Muscular Dystrophy and Limb-Girdle Muscular Dystrophy-1C 
Molecular Biology of the Cell  2003;14(10):4075-4088.
Caveolae are vesicular invaginations of the plasma membrane. Caveolin-3 is the principal structural component of caveolae in skeletal muscle cells in vivo. We have recently generated caveolin-3 transgenic mice and demonstrated that overexpression of wild-type caveolin-3 in skeletal muscle fibers is sufficient to induce a Duchenne-like muscular dystrophy phenotype. In addition, we have shown that caveolin-3 null mice display mild muscle fiber degeneration and T-tubule system abnormalities. These data are consistent with the mild phenotype observed in Limb-girdle muscular dystrophy-1C (LGMD-1C) in humans, characterized by a ∼95% reduction of caveolin-3 expression. Thus, caveolin-3 transgenic and null mice represent valid mouse models to study Duchenne muscular dystrophy (DMD) and LGMD-1C, respectively, in humans. Here, we derived conditionally immortalized precursor skeletal muscle cells from caveolin-3 transgenic and null mice. We show that overexpression of caveolin-3 inhibits myoblast fusion to multinucleated myotubes and lack of caveolin-3 enhances the fusion process. M-cadherin and microtubules have been proposed to mediate the fusion of myoblasts to myotubes. Interestingly, we show that M-cadherin is downregulated in caveolin-3 transgenic cells and upregulated in caveolin-3 null cells. For the first time, variations of M-cadherin expression have been linked to a muscular dystrophy phenotype. In addition, we demonstrate that microtubules are disorganized in caveolin-3 null myotubes, indicating the importance of the cytoskeleton network in mediating the phenotype observed in these cells. Taken together, these results propose caveolin-3 as a key player in myoblast fusion and suggest that defects of the fusion process may represent additional molecular mechanisms underlying the pathogenesis of DMD and LGMD-1C in humans.
PMCID: PMC207001  PMID: 14517320
17.  Congenital Muscular Dystrophies Involving the O-Mannose Pathway 
Current molecular medicine  2007;7(4):417-425.
A number of forms of congenital muscular dystrophy (CMD) have been identified that involve defects in the glycosylation of dystroglycan with O-mannosyl-linked glycans. There are at least six genes that can affect this type of glycosylation, and defects in these genes give rise to disorders that have many aspects of muscle and brain pathology in common. Overexpression of one gene implicated in CMD, LARGE, was recently shown to increase dystroglycan glycosylation and restore its function in cells taken from CMD patients. Overexpression of Galgt2, a glycosyltransferase not implicated in CMD, also alters dystroglycan glycosylation and inhibits muscular dystrophy in a mouse model of Duchenne muscular dystrophy. These findings suggest that a common approach to therapy in muscular dystrophies may be to increase the glycosylation of dystroglycan with particular glycan structures.
PMCID: PMC2855644  PMID: 17584082
18.  Proteomic Profiling of the Dystrophin-Deficient mdx Phenocopy of Dystrophinopathy-Associated Cardiomyopathy 
BioMed Research International  2014;2014:246195.
Cardiorespiratory complications are frequent symptoms of Duchenne muscular dystrophy, a neuromuscular disorder caused by primary abnormalities in the dystrophin gene. Loss of cardiac dystrophin initially leads to changes in dystrophin-associated glycoproteins and subsequently triggers secondarily sarcolemmal disintegration, fibre necrosis, fibrosis, fatty tissue replacement, and interstitial inflammation. This results in progressive cardiac disease, which is the cause of death in a considerable number of patients afflicted with X-linked muscular dystrophy. In order to better define the molecular pathogenesis of this type of cardiomyopathy, several studies have applied mass spectrometry-based proteomics to determine proteome-wide alterations in dystrophinopathy-associated cardiomyopathy. Proteomic studies included both gel-based and label-free mass spectrometric surveys of dystrophin-deficient heart muscle from the established mdx animal model of dystrophinopathy. Comparative cardiac proteomics revealed novel changes in proteins associated with mitochondrial energy metabolism, glycolysis, signaling, iron binding, antibody response, fibre contraction, basal lamina stabilisation, and cytoskeletal organisation. This review summarizes the importance of studying cardiomyopathy within the field of muscular dystrophy research, outlines key features of the mdx heart and its suitability as a model system for studying cardiac pathogenesis, and discusses the impact of recent proteomic findings for exploring molecular and cellular aspects of cardiac abnormalities in inherited muscular dystrophies.
PMCID: PMC3977469  PMID: 24772416
19.  Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population 
Brain : a journal of neurology  2009;132(0 11):3175-3186.
We have performed a detailed population study of patients with genetic muscle disease in the northern region of England. Our current clinic population comprises over 1100 patients in whom we have molecularly characterized 31 separate muscle disease entities. Diagnostic clarity achieved through careful delineation of clinical features supported by histological, immunological and genetic analysis has allowed us to reach a definitive diagnosis in 75.7% of our patients. We have compared our case profile with that from Walton and Nattrass’ seminal study from 1954, also of the northern region, together with data from other more recent studies from around the world. Point prevalence figures for each of the five major disease categories are comparable with those from other recent studies. Myotonic dystrophies are the most common, comprising 28.6% of our clinic population with a point prevalence of 10.6/100 000. Next most frequent are the dystrophinopathies and facioscapulohumeral muscular dystrophy making up 22.9% (8.46/100 000) and 10.7% (3.95/100 000) of the clinic population, respectively. Spinal muscular atrophy patients account for 5.1% or 1.87/100 000 patients. Limb girdle muscular dystrophy, which was described for the first time in the paper by Walton and Nattrass (1954) and comprised 17% of their clinic population, comprises 6.2% of our clinic population at a combined prevalence of 2.27/100 000. The clinic population included patients with 12 other muscle disorders. These disorders ranged from a point prevalence of 0.89/100 000 for the group of congenital muscular dystrophies to conditions with only two affected individuals in a population of three million. For the first time our study provides epidemiological information for X-linked Emery–Dreifuss muscular dystrophy and the collagen VI disorders. Each of the X-linked form of Emery–Dreifuss muscular dystrophy and Ullrich muscular dystrophy has a prevalence of 0.13/100 000, making both very rare. Bethlem myopathy was relatively more common with a prevalence of 0.77/100 000. Overall our study provides comprehensive epidemiological information on individually rare inherited neuromuscular conditions in Northern England. Despite the deliberate exclusion of relatively common groups such as hereditary motor and sensory neuropathy (40/100 000) and mitochondrial disorders (9.2/100 000), the combined prevalence is 37.0/100 000, demonstrating that these disorders, taken as a group, encompass a significant proportion of patients with chronic disease. The study also illustrates the immense diagnostic progress since the first regional survey over 50 years ago by Walton and Nattrass.
PMCID: PMC4038491  PMID: 19767415
population study; prevalence; Northern England; inherited neuromuscular diseases; muscular dystrophy
20.  The Dystrophin Complex Controls BK Channel Localization and Muscle Activity in Caenorhabditis elegans 
PLoS Genetics  2009;5(12):e1000780.
Genetic defects in the dystrophin-associated protein complex (DAPC) are responsible for a variety of pathological conditions including muscular dystrophy, cardiomyopathy, and vasospasm. Conserved DAPC components from humans to Caenorhabditis elegans suggest a similar molecular function. C. elegans DAPC mutants exhibit a unique locomotory deficit resulting from prolonged muscle excitation and contraction. Here we show that the C. elegans DAPC is essential for proper localization of SLO-1, the large conductance, voltage-, and calcium-dependent potassium (BK) channel, which conducts a major outward rectifying current in muscle under the normal physiological condition. Through analysis of mutants with the same phenotype as the DAPC mutants, we identified the novel islo-1 gene that encodes a protein with two predicted transmembrane domains. We demonstrate that ISLO-1 acts as a novel adapter molecule that links the DAPC to SLO-1 in muscle. We show that a defect in either the DAPC or ISLO-1 disrupts normal SLO-1 localization in muscle. Consistent with observations that SLO-1 requires a high calcium concentration for full activation, we find that SLO-1 is localized near L-type calcium channels in muscle, thereby providing a mechanism coupling calcium influx with the outward rectifying current. Our results indicate that the DAPC modulates muscle excitability by localizing the SLO-1 channel to calcium-rich regions of C. elegans muscle.
Author Summary
Dystrophin is a long rod-shaped protein that forms a complex with several membrane and cytoplasmic proteins in muscle. Genetic defects in components of this dystrophin complex are responsible for many forms of muscular dystrophy, including Duchenne muscular dystrophy. C. elegans possesses the dystrophin complex and mutations in its components cause muscular defects, indicating that the dystrophin complex has an evolutionary conserved role in muscle. Accumulating evidence in mammals indicates that dystrophic muscle exhibits an abnormal calcium homeostasis. It is not clear how defects in the dystrophin complex are linked to calcium homeostasis, however. In a C. elegans genetic study we found that a novel adaptor protein links the dystrophin complex to a calcium-sensitive potassium channel that mediates muscle inactivation. We further demonstrated that both the dystrophin complex and the adaptor protein localize the potassium channel in a close proximity to a muscle-activating calcium channel. This arrangement ensures that calcium increases accompanied by muscle activation are coupled to muscle inactivation. Defects in the dystrophin complex or the adaptor disrupt the localization of the potassium channel, thereby resulting in prolonged muscle activation and calcium ion increases. Our study provides a mechanism by which the dystrophin complex regulates cellular signaling and muscle excitability.
PMCID: PMC2788698  PMID: 20019812
21.  Linking cytoarchitecture to metabolism: sarcolemma-associated plectin affects glucose uptake by destabilizing microtubule networks in mdx myofibers 
Skeletal Muscle  2013;3:14.
Duchenne muscular dystrophy (DMD) is one of the most frequent forms of muscular disorders. It is caused by the absence of dystrophin, a core component of the sarcolemma-associated junctional complex that links the cytoskeleton to the extracellular matrix. We showed previously that plectin 1f (P1f), one of the major muscle-expressed isoforms of the cytoskeletal linker protein plectin, accumulates at the sarcolemma of DMD patients as well as of mdx mice, a widely studied animal model for DMD.
Based on plectin’s dual role as structural protein and scaffolding platform for signaling molecules, we speculated that the dystrophic phenotype observed after loss of dystrophin was caused, at least to some extent, by excess plectin. Thus, we hypothesized that elimination of plectin expression in mdx skeletal muscle, while probably resulting in an overall more severe phenotype, may lead to a partial phenotype rescue. In particular, we wanted to assess whether excess sarcolemmal plectin contributes to the dysregulation of sugar metabolism in mdx myofibers.
We generated plectin/dystrophin double deficient (dKO) mice by breeding mdx with conditional striated muscle-restricted plectin knockout (cKO) mice. The phenotype of these mice was comparatively analyzed with that of mdx, cKO, and wild-type mice, focusing on structural integrity and dysregulation of glucose metabolism.
We show that the accumulation of plectin at the sarcolemma of mdx muscle fibers hardly compensated for their loss of structural integrity. Instead, it led to an additional metabolic deficit by impairing glucose uptake. While dKO mice suffered from an overall more severe form of muscular dystrophy compared to mdx or plectin-deficient mice, sarcolemmal integrity as well as glucose uptake of their myofibers were restored to normal levels upon ablation of plectin. Furthermore, microtubule (MT) networks in intact dKO myofibers, including subsarcolemmal areas, were found to be more robust than those in mdx mice. Finally, myotubes differentiated from P1f-overexpressing myoblasts showed an impairment of glucose transporter 4 translocation and a destabilization of MT networks.
Based on these results we propose that sarcolemma-associated plectin acts as an antagonist of MT network formation in myofibers, thereby hindering vesicle-mediated (MT-dependent) transport of glucose transporter 4. This novel role of plectin throws a bridge between extra-sarcomeric cytoarchitecture and metabolism of muscle fibers. Our study thus provides new insights into pathomechanisms of plectinopathies and muscular dystrophies in general.
PMCID: PMC3695810  PMID: 23758845
Plectin; Dystrophin; Sarcolemmal integrity; Glucose metabolism; Microtubules
22.  Identification of Muscle-Specific MicroRNAs in Serum of Muscular Dystrophy Animal Models: Promising Novel Blood-Based Markers for Muscular Dystrophy 
PLoS ONE  2011;6(3):e18388.
Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder caused by mutations in the dystrophin gene, which encodes a cytoskeletal protein, dystrophin. Creatine kinase (CK) is generally used as a blood-based biomarker for muscular disease including DMD, but it is not always reliable since it is easily affected by stress to the body, such as exercise. Therefore, more reliable biomarkers of muscular dystrophy have long been desired. MicroRNAs (miRNAs) are small, ∼22 nucleotide, noncoding RNAs which play important roles in the regulation of gene expression at the post-transcriptional level. Recently, it has been reported that miRNAs exist in blood. In this study, we hypothesized that the expression levels of specific serum circulating miRNAs may be useful to monitor the pathological progression of muscular diseases, and therefore explored the possibility of these miRNAs as new biomarkers for muscular diseases. To confirm this hypothesis, we quantified the expression levels of miRNAs in serum of the dystrophin-deficient muscular dystrophy mouse model, mdx, and the canine X-linked muscular dystrophy in Japan dog model (CXMDJ), by real-time PCR. We found that the serum levels of several muscle-specific miRNAs (miR-1, miR-133a and miR-206) are increased in both mdx and CXMDJ. Interestingly, unlike CK levels, expression levels of these miRNAs in mdx serum are little influenced by exercise using treadmill. These results suggest that serum miRNAs are useful and reliable biomarkers for muscular dystrophy.
PMCID: PMC3068182  PMID: 21479190
23.  Long term non-invasive ventilation in the community for patients with musculoskeletal disorders: 46 year experience and review 
Thorax  2000;55(1):4-11.
BACKGROUND—A study was undertaken to assess the long term physiological and clinical outcome in 79 patients with musculoskeletal disorders (73 neuromuscular, six of the chest wall) who received non-invasive ventilation for chronic respiratory failure over a period of 46years.
METHODS—Vital capacity (VC) and carbon dioxide tension (PCO2) before and after initiation of ventilation, type and duration of ventilatory assistance, the need for tracheostomy, and mortality were retrospectively studied in 48 patients who were managed with mouth/nasal intermittent positive pressure ventilation (M/NIPPV) and 31 who received body ventilation. The two largest groups analysed were 45 patients with poliomyelitis and 15 with Duchenne's muscular dystrophy. Twenty five patients with poliomyelitis received body ventilation (for a mean of 290 months) and 20 were supported by M/NIPPV (mean 38 months). All 15 patients with Duchenne's muscular dystrophy were ventilated by NIPPV (mean 22months).
RESULTS—Fourteen patients with poliomyelitis on body ventilation (56%) but only one on M/NIPPV, and 10 of 15 patients (67%) with Duchenne's muscular dystrophy eventually received tracheostomies for ventilatory support. Five patients with other neuromuscular disorders required tracheostomies. Twenty of 29 tracheostomies (69%) were provided because of progressive disease and hypercarbia which could not be controlled by non-invasive ventilation; the remaining nine were placed because of bulbar dysfunction and aspiration related complications. Nine of 10 deaths occurred in patients on body ventilation (six with poliomyelitis), although the causes of death were varied and not necessarily related to respiratory complications. A proportionately greater number of patients on M/NIPPV (67%) reported positive outcomes (improved sense of wellbeing and independence) than did those on body ventilation (29%, p<0.01). However, other than tracheostomies and deaths, negative outcomes in the form of machine/interface discomfort and self-discontinuation of ventilation also occurred at a rate 2.3 times higher than in the group who received body ventilation. None of the six patients with chest wall disorders (all on M/NIPPV) required tracheostomy or died. Hospital admission rates increased nearly eightfold in patients receiving body ventilation (all poliomyelitis patients) compared with before ventilation (p<0.01) while in those supported by M/NIPPV they were reduced by 36%.
CONCLUSIONS—Non-invasive ventilation (NIV) in the community over prolonged periods is a feasible although variably tolerated form of management in patients with neuromuscular disorders. While patients who received body ventilation were followed the longest (mean 24 years), the need for tracheostomy and deaths occurred more often in this group (most commonly in the poliomyelitis patients). Despite a number of discomforts associated with M/NIPPV, a larger proportion of patients experienced improved wellbeing, independence, and ability to perform daily activities.

PMCID: PMC1745585  PMID: 10607795
24.  Cardiac Dysrhythmias, Cardiomyopathy and Muscular Dystrophy in Patients with Emery-Dreifuss Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type 1B 
Journal of Korean Medical Science  2005;20(2):283-290.
Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy type 1B (LGMD1B) are characterized by cardiac dysrhythmias, late-onset cardiomyopathy, slowly progressive skeletal myopathy and contractures of the neck, elbows and ankles. The causative mutation is either in the emerin gene (X-linked recessive EDMD) or lamin A/C gene (autosomal dominant EDMD2 or LGMD1B). We report three cases of EDMD, EDMD2 and LGMD1B. A 14-yr-old boy showed limitation of cervical flexion and contractures of both elbows and ankles. Sinus arrest with junctional escape beats was noted. He was diagnosed as X-linked recessive EDMD (MIM 310300). A 28-yr-old female showed severe wasting and weakness of humeroperoneal muscles. Marked limitation of cervical flexion and contractures of both elbows and ankles were noted. Varying degrees of AV block were noted. She was diagnosed as autosomal dominant EDMD2 (MIM 181350). A 41-yr-old female had contractures of both ankles and limb-girdle type muscular dystrophy. ECG revealed atrial tachycardia with high grade AV block. She was diagnosed as autosomal dominant LGMD1B (MIM 159001). Cardiac dysrhythmias in EDMD and LGMD1B include AV block, bradycardia, atrial tachycardia, atrial fibrillation, and atrial standstill, causing sudden death necessitating pacemaker implantation. Cardiologists should know about these unusual genetic diseases with conduction defects, especially in young adults.
PMCID: PMC2808607  PMID: 15832002
Muscular Dystrophies; Cardiomyopathies; emerin; Lamins; Heart Conduction System
25.  Modifiers of Heart and Muscle Function: Where Genetics Meets Physiology 
Experimental physiology  2013;99(4):621-626.
Many single gene disorders are associated with a range of symptoms that cannot be solely explained by the primary genetic mutation. Muscular dystrophy is a genetic disorder associated with variable outcomes that arises from both the primary genetic mutation and the contribution from environmental and genetic modifiers. Disruption of the dystrophin complex occurs in Duchenne muscular dystrophy and limb girdle muscular dystrophy producing heart and muscle disease through a cellular injury process characterized by plasma membrane disruption and fibrosis. Multiple modifier loci have been mapped by using a mouse model of muscular dystrophy. These modifiers exert their effect often on specific muscle groups targeted by the muscular dystrophy process, possibly reflecting distinct pathophysiological processes among muscle groups. Genetic modifiers act on both cardiac and respiratory muscle parameters suggesting genetic and physiological integration of cardiopulmonary function. Skeletal muscles of the limbs are modified by a locus on mouse chromosome 7. This region of chromosome 7 harbors an insertion/deletion polymorphism in Ltbp4, the gene encoding latent TGFβ binding protein. Ltbp4 exerts its effect in muscle disease by acting on plasma membrane stability and fibrosis, thereby linking instability of the sarcolemma directly to fibrosis. In the human muscle disease Duchenne Muscular Dystrophy, protein coding single nucleotide polymorphisms in LTBP4 associate with prolonged ambulation demonstrating that modifiers identified from mouse studies translate to human disease.
PMCID: PMC3975685  PMID: 24213858
muscular dystrophy; genetic modifiers; cardiopulmonary function

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