Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy

10.1038/6799 ◽  
1999 ◽  
Vol 21 (3) ◽  
pp. 285-288 ◽  
Author(s):  
Gisèle Bonne ◽  
Marina Raffaele Di Barletta ◽  
Shaida Varnous ◽  
Henri-Marc Bécane ◽  
El-Hadi Hammouda ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Autosomal Dominant ◽  
Lamin A ◽  
Gene Encoding

Investigating the pathology of Emery–Dreifuss muscular dystrophy

2008 ◽  
Vol 36 (6) ◽  
pp. 1335-1338 ◽  
Author(s):  
Susan C. Brown ◽  
Richard J. Piercy ◽  
Francesco Muntoni ◽  
Caroline A. Sewry
Keyword(s):  
Muscular Dystrophy ◽  
Animal Models ◽  
Genetic Background ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Clinical Severity ◽  
Lamin A ◽  
Pathological Findings ◽  
Gene Encoding ◽  
Insight Into

EDMD (Emery–Dreifuss muscular dystrophy) is caused by mutations in either the gene encoding for lamin A/C (LMNA) located at 1q21.2–q21.3 or emerin (EMD) located at Xq28. Autosomal dominant EDMD caused by LMNA mutations is more common than the X-linked form and often more severe, with an earlier onset. At the histological and histochemical levels, both X-linked and autosomal dominant EDMD appear similar. However, individuals with the same genetic disorder often show remarkable differences in clinical severity, a finding generally attributed to the genetic background. The clinical and pathological findings in EDMD patients found to have mutations in more than one gene are also discussed. There is now much interest in the phenotype of several animal models for EDMD which should lead to an increased insight into the pathogenesis of this disorder, particularly that relating to the heart phenotype.

scholarly journals Postnatal development of mice with combined genetic depletions of lamin A/C, emerin and lamina-associated polypeptide 1

2019 ◽  
Vol 28 (15) ◽  
pp. 2486-2500 ◽  
Author(s):  
Yuexia Wang ◽  
Ji-Yeon Shin ◽  
Koki Nakanishi ◽  
Shunichi Homma ◽  
Grace J Kim ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Left Ventricular Function ◽  
Left Ventricular ◽  
Lamin A ◽  
Heterozygous Deletion ◽  
Gene Encoding ◽  
Heart Ultrastructure ◽  
Electrocardiographic Parameters ◽  
Normal Embryonic Development

Abstract Mutations in LMNA encoding lamin A/C and EMD encoding emerin cause cardiomyopathy and muscular dystrophy. Lmna null mice develop these disorders and have a lifespan of 7–8 weeks. Emd null mice show no overt pathology and have normal skeletal muscle but with regeneration defects. We generated mice with germline deletions of both Lmna and Emd to determine the effects of combined loss of the encoded proteins. Mice without lamin A/C and emerin are born at the expected Mendelian ratio, are grossly normal at birth but have shorter lifespans than those lacking only lamin A/C. However, there are no major differences between these mice with regards to left ventricular function, heart ultrastructure or electrocardiographic parameters except for slower heart rates in the mice lacking both lamin A/C and emerin. Skeletal muscle is similarly affected in both of these mice. Lmna+/− mice also lacking emerin live to at least 1 year and have no significant differences in growth, heart or skeletal muscle compared to Lmna+/− mice. Deletion of the mouse gene encoding lamina-associated protein 1 leads to prenatal death; however, mice with heterozygous deletion of this gene lacking both lamin A/C and emerin are born at the expected Mendelian ratio but had a shorter lifespan than those only lacking lamin A/C and emerin. These results show that mice with combined deficiencies of three interacting nuclear envelope proteins have normal embryonic development and that early postnatal defects are primarily driven by loss of lamin A/C or lamina-associated polypeptide 1 rather than emerin.

Molecular signatures of Emery–Dreifuss muscular dystrophy

2008 ◽  
Vol 36 (6) ◽  
pp. 1354-1358 ◽  
Author(s):  
Matthew A. Wheeler ◽  
Juliet A. Ellis
Keyword(s):  
Muscular Dystrophy ◽  
Dilated Cardiomyopathy ◽  
Molecular Mechanisms ◽  
Autosomal Dominant ◽  
Signalling Pathways ◽  
Lamin A ◽  
Degenerative Diseases ◽  
Hypertrophic Growth ◽  
Genes Encoding

Mutations in genes encoding the nuclear envelope proteins emerin and lamin A/C lead to a range of tissue-specific degenerative diseases. These include dilated cardiomyopathy, limb-girdle muscular dystrophy and X-linked and autosomal dominant EDMD (Emery–Dreifuss muscular dystrophy). The molecular mechanisms underlying these disorders are poorly understood; however, recent work using animal models has identified a number of signalling pathways that are altered in response to the deletion of either emerin or lamin A/C or expression of Lmna mutants found in patients with laminopathies. A distinguishing feature of patients with EDMD is the association of a dilated cardiomyopathy with conduction defects. In the present article, we describe several of the pathways altered in response to an EDMD phenotype, which are known to be key mediators of hypertrophic growth, and focus on a possible role of an emerin–β-catenin interaction in the pathogenesis of this disease.

scholarly journals Emery-Dreifuss Muscular Dystrophy-Associated Mutant Forms of Lamin A Recruit the Stress Responsive Protein Ankrd2 into the Nucleus, Affecting the Cellular Response to Oxidative Stress

2017 ◽  
Vol 42 (1) ◽  
pp. 169-184 ◽  
Author(s):  
Silvia Angori ◽  
Cristina Capanni ◽  
Georgine Faulkner ◽  
Camilla Bean ◽  
Giuseppe Boriani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Muscular Dystrophy ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Muscle Cells ◽  
Lamin A ◽  
Gene Encoding ◽  
H2o2 Treatment ◽  
Human Myotubes ◽  
Mutant Forms

Background: Ankrd2 is a stress responsive protein mainly expressed in muscle cells. Upon the application of oxidative stress, Ankrd2 translocates into the nucleus where it regulates the activity of genes involved in cellular response to stress. Emery-Dreifuss Muscular Dystrophy 2 (EDMD2) is a muscular disorder caused by mutations of the gene encoding lamin A, LMNA. As well as many phenotypic abnormalities, EDMD2 muscle cells also feature a permanent basal stress state, the underlying molecular mechanisms of which are currently unclear. Methods: Experiments were performed in EDMD2-lamin A overexpressing cell lines and EDMD2-affected human myotubes. Oxidative stress was produced by H2O2 treatment. Co-immunoprecipitation, cellular subfractionation and immunofluorescence analysis were used to validate the relation between Ankrd2 and forms of lamin A; cellular sensibility to stress was monitored by the analysis of Reactive Oxygen Species (ROS) release and cell viability. Results: Our data demonstrate that oxidative stress induces the formation of a complex between Ankrd2 and lamin A. However, EDMD2-lamin A mutants were able to bind and mislocalize Ankrd2 in the nucleus even under basal conditions. Nonetheless, cells co-expressing Ankrd2 and EDMD2-lamin A mutants were more sensitive to oxidative stress than the Ankrd2-wild type lamin A counterpart. Conclusions: For the first time, we present evidence that in muscle fibers from patients affected by EDMD2, Ankrd2 has an unusual nuclear localization. By introducing a plausible mechanism ruling this accumulation, our data hint at a novel function of Ankrd2 in the pathogenesis of EDMD2-affected cells.

Nuclear envelope defects associated withLMNAmutations cause dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy

2001 ◽  
Vol 114 (24) ◽  
pp. 4447-4457 ◽  
Author(s):  
Wahyu Hendrati Raharjo ◽  
Paul Enarson ◽  
Teresa Sullivan ◽  
Colin L. Stewart ◽  
Brian Burke
Keyword(s):  
Muscular Dystrophy ◽  
Dilated Cardiomyopathy ◽  
Hela Cells ◽  
Autosomal Dominant ◽  
Nuclear Periphery ◽  
Point Mutations ◽  
Molecular Organization ◽  
Structural Defects ◽  
Lamin A ◽  
Dominant Form

Nuclear lamin A and C alleles that are linked to three distinct human diseases have been expressed both in HeLa cells and in fibroblasts derived from Lmna null mice. Point mutations that cause dilated cardiomyopathy (L85R and N195K) and autosomal dominant Emery-Dreifuss muscular dystrophy (L530P) modify the assembly properties of lamins A and C and cause partial mislocalization of emerin, an inner nuclear membrane protein, in HeLa cells. At the same time, these mutant lamins interfere with the targeting and assembly of endogenous lamins and in this way may cause significant changes in the molecular organization of the nuclear periphery. By contrast, lamin A and C molecules harboring a point mutation (R482W), which gives rise to a dominant form of familial partial lipodystrophy, behave in a manner that is indistinguishable from wild-type lamins A and C, at least with respect to targeting and assembly within the nuclear lamina. Taken together, these results suggest that nuclear structural defects could contribute to the etiology of both dilated cardiomyopathy and autosomal dominant Emery-Dreifuss muscular dystrophy.

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

2017 ◽  
Vol 6 (1) ◽  
pp. 14-18
Author(s):  
Elise Alexandra Kikis ◽  
Megan Elizabeth Mastey
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Envelope ◽  
Autosomal Dominant ◽  
Nuclear Lamina ◽  
Autosomal Recessive Inheritance ◽  
Envelope Proteins ◽  
Lamin A ◽  
Dominant Form ◽  
Specific Effects ◽  
Autosomal Dominant Form

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.

Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene

2000 ◽  
Vol 48 (2) ◽  
pp. 170-180 ◽  
Author(s):  
G. Bonne ◽  
E. Mercuri ◽  
A. Muchir ◽  
A. Urtizberea ◽  
H. M. B�cane ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Autosomal Dominant ◽  
Molecular Genetic ◽  
Lamin A
Sign in / Sign up

Export Citation Format

Share Document