X-linked Form Of Emery-Dreifuss Muscular Dystrophy Research Articles

The Genes, Proteins, and the Cell Biological Processes Underlying Emery-Dreifuss Muscular Dystrophy

Emery-Dreifuss Muscular Dystrophy (EDMD) is a type of muscular dystrophy characterized by contractures, or shortening of muscles or joints in the elbows and Achilles tendons, muscle wasting and weakness as well as cardiomyopathy. There are two main forms of inherited EDMD, X-linked recessive and autosomal dominant. There is also a rarer form of autosomal recessive inheritance with only a few cases ever reported. The X-linked form of EDMD is caused by mutation of the STA gene that encodes the protein emerin, while the autosomal dominant form is caused by a missense mutation on the LMNA gene, which encodes lamin A/C proteins. Both emerin and lamin A/C are nuclear envelope proteins that interact with other proteins to create a connective network that attaches the nuclear lamina to the cytoskeleton. These nuclear envelope proteins interact via accessory proteins to chromatin and also thereby stimulate gene expression. The exact mechanism of how mutations in these genes lead to muscular dystrophy is not well understood. The “structural hypothesis,” states that the absence of these envelope proteins result in a weakened cell and would eventually end in nuclear disruption. The “gene regulatory hypothesis” states that emerin and lamin may be transcription factors whose absence results in tissue-specific effects. This review will addresses these hypotheses, describes what is known about the cell and molecular biology underlying EDMD and considers recent as advances in therapeutics.

Semaphorin 3A promotes activation of Pax7, Myf5, and MyoD through inhibition of emerin expression in activated satellite cells.

We previously showed that Semaphorin 3A (Sema3A) expression was induced when quiescent muscle satellite cells were stimulated by hepatocyte growth factor and became activated satellite cells (ASCs). However, how Sema3A regulates genes in the early phase of ASCs remains unclear. In this study, we investigated whether Sema3A signaling can regulate the early phase of ASCs, an important satellite cell stage for postnatal growth, repair, and maintenance of skeletal muscle. We showed that expression of the myogenic proliferation regulatory factors Pax7 and Myf5 was decreased in myoblasts transfected with Sema3A siRNA. These cells failed to activate expression MyoD, another myogenic proliferation regulatory factor, during differentiation. Interestingly, some of the Sema3A‐depleted cells did not express Pax7 and MyoD and had enlarged nuclei and very large cytoplasmic areas. We also observed that Pax7 and Myf5 expression was increased in Myc‐Sema3A overexpressing myoblasts. BrdU analysis indicated that Sema3A regulated proliferation of ASCs. These findings suggest that Sema3A signaling can modulate expression of Pax7, Myf5, and MyoD. Moreover, we found that expression of emerin, an inner nuclear membrane protein, was regulated by Sema3A signaling. Emerin was identified by positional cloning as the gene responsible for the X‐linked form of Emery–Dreifuss muscular dystrophy (X‐EDMD). In conclusion, our results support a role for Sema3A in maintaining ASCs through regulation, via emerin, of Pax7, Myf5, and MyoD expression.

Emery–Dreifuss muscular dystrophy with cardiac manifestations

An asymptomatic 40-year-old man attended clinic for cardiology assessment before cataract surgery. He had been diagnosed 9 years earlier with a ‘non specified limb-girdle muscular dystrophy’ following investigation for lower limb muscle weakness. Earlier electrocardiograms (ECGs) showed a bradycardic, junctional escape rhythm of 30–40 beats per minute (BPM). He had previously refused pacemaker insertion. He denied any syncope, shortness of breath or palpitations. He had muscle wasting to his upper arms and calves plus mild elbow contractures. He was normotensive, resting regular heart rate = 42 BPM and cardiorespiratory examination was unremarkable. His ECG showed atrial fibrillation, with a slow junctional escape rhythm of approximately 40 BPM and normal QRS width (Figure 1). Blood tests showed no haematological, electrolyte or thyroid dysfunction and no impaired glucose tolerance. Echocardiography showed good left ventricular function and 24-hour ECG Holter monitoring showed 8 pauses (longest 2.13s), with a heart rate varying between 29 and 79 BPM. He was commenced on clopidogrel to prevent thromboembolic complications and then he agreed for a VVIR system to be implanted to avoid bradyarrhythmic death. No complications ensued and he remains well at present. The patient also had two brothers, one died suddenly and the cause of death was not clearly determined. His elder brother was 52 years old and was diagnosed with a non-specific muscular dystrophy also associated with a junctional rhythm. He had a VVIR permanent pacemaker inserted in April 2003 following recurrent episodes of dizziness. An hereditary skeletal myopathy in association with pathognomic cardiac abnormalities suggested a diagnosis of Emery–Dreifuss muscular dystrophy (EDMD). Prognostically and therapeutically a definitive genetic diagnosis was required. Genetic testing confirmed that both siblings had inherited the X-linked form of EDMD involving a single base change of the emerin gene.

108th ENMC International Workshop, 3rd Workshop of the MYO-CLUSTER project: EUROMEN, 7th International Emery-Dreifuss Muscular Dystrophy (EDMD) Workshop, 13–15 September 2002, Naarden, The Netherlands

Inserm UR582 (ex 523), Institut de Myologie, Bâtiment Babinski, G.H. Pitie-Salpetriere, 47, boulevard de l’Hopital, 75 651 Paris Cedex 13, France Laboratoire de Genetique Moleculaire et Chromosomique, IURC, Montpellier, France Institute of Cardiology, University of Bologna, Bologna, Italy Department of Paediatrics and Neonatal Medicine, Imperial College School of Medicine, Hammersmith Campus, London, UK Department of Neurology, Academic Medical Centre, Amsterdam, The Netherlands Service de Cardiologie, GH Cochin, Paris, France Randall Center, Kings College, London, UK Neuromuscular Unit, M.R.C. Polish Academy of Sciences, Warsaw, Poland ITOI, Unit of Bologna, c/o IOR, Bologna, Italy Istituto Ortopedico Rizzoli, Neuromuscular Unit, Bologna, Italy MRIC, North East Wales Institute, Wrexham, UK Department of Internal Medicine and Cardiology Medical University of Warsaw, Warsaw, Poland Department of Cardiology, University Hospital Maastricht, Maastricht, The Netherlands Dipartimento di Biopatologia e Diagnostica per Immagini, Rome, Italy Istituto di Genetica Biochimica ed Evoluzionistica, CNR (IGBE-CNR), Pavia, Italy Division of Medical Genetics, University of Leicester, Leicester, UK Institute of Human Genetics, Greifswald, Germany

Structural analysis of emerin, an inner nuclear membrane protein mutated in X-linked Emery–Dreifuss muscular dystrophy

Like Duchenne and Becker muscular dystrophies, Emery–Dreifuss muscular dystrophy (EDMD) is characterized by myopathic and cardiomyopathic abnormalities. EDMD has the particularity of being linked to mutations in nuclear proteins. The X-linked form of EDMD is caused by mutations in the emerin gene, whereas autosomal dominant EDMD is caused by mutations in the lamin A/C gene. Emerin colocalizes with lamin A/C in interphase cells, and binds in vitro to lamin A/C. Recent work suggests that lamin A/C might serve as a receptor for emerin. We have undertaken a structural analysis of emerin, and in particular of its N-terminal domain, which is comprised in the emerin segment critical for binding to lamin A/C. We show that region 2–54 of emerin adopts the LEM fold. This fold was originally described in the two N-terminal domains of another inner nuclear membrane protein called lamina-associated protein 2 (LAP2). The existence of a conserved solvent-exposed surface on the LEM domains of LAP2 and emerin is discussed, as well as the nature of a possible common target.

Oral exfoliative cytology for the non-invasive diagnosis in X-linked Emery–Dreifuss muscular dystrophy patients and carriers

Emery–Dreifuss muscular dystrophy (EMD) is an inherited myopathy characterised by muscle contractures, progressive muscle wasting and weakness, with humeroperoneal distribution. Cardiac arrhythmia and heart conduction block are also important characteristics of this disease. The X-linked form of EMD is caused by the absence of emerin, encoded by the STA gene (Xq28). Emerin is normally localised in muscle and other tissues at the nuclear rim. Currently, muscle and skin biopsies are used for the immunohistochemical diagnosis. We demonstrate that emerin is present in the cheek oral mucosa, in the exfoliating epithelial cells, and we propose the collection of these cells as a new method for the diagnosis of X-linked EMD patients and the detection of carriers by immunofluorescence techniques: smears from healthy subjects contained about 98% emerin-positive cells, those from X-linked EMD patients contained none and those from carriers contained about 45%. The technique is completely non-invasive, simple, repeatable and inexpensive.