Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins

Intermediate filaments are major components of the cytoskeleton. Desmin and synemin, cytoplasmic intermediate filament proteins and A-type lamins, nuclear intermediate filament proteins, play key roles in skeletal and cardiac muscle. Desmin, encoded by the DES gene (OMIM *125660) and A-type lamins by the LMNA gene (OMIM *150330), have been involved in striated muscle disorders. Diseases include desmin-related myopathy and cardiomyopathy (desminopathy), which can be manifested with dilated, restrictive, hypertrophic, arrhythmogenic, or even left ventricular non-compaction cardiomyopathy, Emery–Dreifuss Muscular Dystrophy (EDMD2 and EDMD3, due to LMNA mutations), LMNA-related congenital Muscular Dystrophy (L-CMD) and LMNA-linked dilated cardiomyopathy with conduction system defects (CMD1A). Recently, mutations in synemin (SYNM gene, OMIM *606087) have been linked to cardiomyopathy. This review will summarize clinical and molecular aspects of desmin-, lamin- and synemin-related striated muscle disorders with focus on LMNA and DES-associated clinical entities and will suggest pathogenetic hypotheses based on the interplay of desmin and lamin A/C. In healthy muscle, such interplay is responsible for the involvement of this network in mechanosignaling, nuclear positioning and mitochondrial homeostasis, while in disease it is disturbed, leading to myocyte death and activation of inflammation and the associated secretome alterations.

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Lamin A/C Assembly Defects in LMNA-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery–Dreifuss Muscular Dystrophy

Cells ◽

10.3390/cells9040844 ◽

2020 ◽

Vol 9 (4) ◽

pp. 844 ◽

Cited By ~ 6

Author(s):

Anne T. Bertrand ◽

Astrid Brull ◽

Feriel Azibani ◽

Louise Benarroch ◽

Khadija Chikhaoui ◽

...

Keyword(s):

Muscular Dystrophy ◽

Striated Muscle ◽

Congenital Muscular Dystrophy ◽

In Silico Analysis ◽

Nuclear Lamina ◽

Lamin A ◽

Muscle Disorders ◽

Severity Of The Disease ◽

Type V ◽

Tetramer Stability

LMNA encodes for Lamin A/C, type V intermediate filaments that polymerize under the inner nuclear membrane to form the nuclear lamina. A small fraction of Lamin A/C, less polymerized, is also found in the nucleoplasm. Lamin A/C functions include roles in nuclear resistance to mechanical stress and gene regulation. LMNA mutations are responsible for a wide variety of pathologies, including Emery–Dreifuss (EDMD) and LMNA-related congenital muscular dystrophies (L-CMD) without clear genotype–phenotype correlations. Both diseases presented with striated muscle disorders although L-CMD symptoms appear much earlier and are more severe. Seeking for pathomechanical differences to explain the severity of L-CMD mutations, we performed an in silico analysis of the UMD-LMNA database and found that L-CMD mutations mainly affect residues involved in Lamin dimer and tetramer stability. In line with this, we found increased nucleoplasmic Lamin A/C in L-CMD patient fibroblasts and mouse myoblasts compared to the control and EDMD. L-CMD myoblasts show differentiation defects linked to their inability to upregulate muscle specific nuclear envelope (NE) proteins expression. NE proteins were mislocalized, leading to misshapen nuclei. We conclude that these defects are due to both the absence of Lamin A/C from the nuclear lamina and its maintenance in the nucleoplasm of myotubes.

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Cardiac Emerinopathy

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.120.008712 ◽

2020 ◽

Vol 13 (10) ◽

Cited By ~ 1

Author(s):

Taisuke Ishikawa ◽

Hiroyuki Mishima ◽

Julien Barc ◽

Masanori P. Takahashi ◽

Keiichi Hirono ◽

...

Keyword(s):

Muscular Dystrophy ◽

Left Ventricular ◽

Cardiac Conduction ◽

Conduction Disturbance ◽

Ventricular Noncompaction ◽

Increased Risk ◽

Genes Encoding ◽

History Of ◽

Cardiac Conduction Defect ◽

Female Carriers

Background: Mutations in the nuclear envelope genes encoding LMNA and EMD are responsible for Emery-Dreifuss muscular dystrophy. However, LMNA mutations often manifest dilated cardiomyopathy with conduction disturbance without obvious skeletal myopathic complications. On the contrary, the phenotypic spectrums of EMD mutations are less clear. Our aims were to determine the prevalence of nonsyndromic forms of emerinopathy, which may underlie genetically undefined isolated cardiac conduction disturbance, and the etiology of thromboembolic complications associated with EMD mutations. Methods: Targeted exon sequencing was performed in 87 probands with familial sick sinus syndrome (n=36) and a progressive cardiac conduction defect (n=51). Results: We identified 3 X-linked recessive EMD mutations (start-loss, splicing, missense) in families with cardiac conduction disease. All 3 probands shared a common clinical phenotype of progressive atrial arrhythmias that ultimately resulted in atrial standstill associated with left ventricular noncompaction (LVNC), but they lacked early contractures and progressive muscle wasting and weakness characteristic of Emery-Dreifuss muscular dystrophy. Because the association of LVNC with EMD has never been reported, we further genetically screened 102 LVNC patients and found a frameshift EMD mutation in a boy with progressive atrial standstill and LVNC without complications of muscular dystrophy. All 6 male EMD mutation carriers of 4 families underwent pacemaker or defibrillator implantation, whereas 2 female carriers were asymptomatic. Notably, a strong family history of stroke observed in these families was probably due to the increased risk of thromboembolism attributable to both atrial standstill and LVNC. Conclusions: Cardiac emerinopathy is a novel nonsyndromic X-linked progressive atrial standstill associated with LVNC and increased risk of thromboembolism.

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Genes encoding cytoplasmic intermediate filament proteins of vertebrates revisited: Identification of a cytoplasmic intermediate filament protein in the sea anemone Nematostella

European Journal of Cell Biology ◽

10.1016/j.ejcb.2012.08.003 ◽

2012 ◽

Vol 91 (10) ◽

pp. 809-817 ◽

Cited By ~ 3

Author(s):

Alexander Zimek ◽

Sören Thiering ◽

Klaus Weber ◽

Thomas M. Magin

Keyword(s):

Intermediate Filament ◽

Sea Anemone ◽

Intermediate Filament Protein ◽

Intermediate Filament Proteins ◽

Genes Encoding ◽

Filament Protein

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Inherited Cardiac Muscle Disorders: Left Ventricular Noncompaction

Cardiovascular Genetics and Genomics ◽

10.1007/978-3-319-66114-8_12 ◽

2018 ◽

pp. 389-412

Author(s):

James Marangou ◽

Michael Frenneaux ◽

Girish Dwivedi

Keyword(s):

Cardiac Muscle ◽

Left Ventricular ◽

Left Ventricular Noncompaction ◽

Ventricular Noncompaction ◽

Muscle Disorders

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Cardiac manifestations of congenital LMNA-related muscular dystrophy in children: three case reports and recommendations for care

Cardiology in the Young ◽

10.1017/s1047951116002079 ◽

2016 ◽

Vol 27 (6) ◽

pp. 1076-1082 ◽

Cited By ~ 7

Author(s):

Felice Heller ◽

Ivana Dabaj ◽

Jean K. Mah ◽

Jean Bergounioux ◽

Aben Essid ◽

...

Keyword(s):

Heart Failure ◽

Muscular Dystrophy ◽

Case Reports ◽

Congenital Muscular Dystrophy ◽

Right Heart Failure ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Rapid Decline ◽

Ventricular Ejection Fraction ◽

Cardiac Manifestations

AbstractSkeletal and cardiac muscle laminopathies, caused by mutations in the lamin A/C gene, have a clinical spectrum from congenital LMNA-related muscular dystrophy to later-onset Emery–Dreifuss muscular dystrophy, limb girdle muscular dystrophy, and dilated cardiomyopathy. Although cardiac involvement is observed at all ages, it has only been well described in adults. We present the evolution of cardiac disease in three children with congenital muscular dystrophy presentation of LMNA-related muscular dystrophy. In this series, atrial arrhythmia was the presenting cardiac finding in all three patients. Heart failure developed up to 5 years later. Symptoms of right heart failure, including diarrhoea and peripheral oedema, preceded a rapid decline in left ventricular ejection fraction. Recommendations for cardiac surveillance and management in these patients are made.

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The role of the GlcNAcβ1,2Manα- moiety in mammalian development. Null mutations of the genes encoding UDP-N-acetylglucosamine:α-3-d-mannoside β-1,2-N-acetylglucosaminyltransferase I and UDP-N-acetylglucosamine:α-d-mannoside β-1,2-N-acetylglucosaminyltransferase I.2 cause embryonic lethality and congenital muscular dystrophy in mice and men, respectively

Biochimica et Biophysica Acta (BBA) - General Subjects ◽

10.1016/s0304-4165(02)00396-3 ◽

2002 ◽

Vol 1573 (3) ◽

pp. 292-300 ◽

Cited By ~ 9

Author(s):

Harry Schachter

Keyword(s):

Muscular Dystrophy ◽

Congenital Muscular Dystrophy ◽

Embryonic Lethality ◽

Mammalian Development ◽

Genes Encoding

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Using nuclear envelope mutations to explore age-related skeletal muscle weakness

Clinical Science ◽

10.1042/cs20190066 ◽

2020 ◽

Vol 134 (16) ◽

pp. 2177-2187

Author(s):

Edmund Battey ◽

Matthew J. Stroud ◽

Julien Ochala

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Nuclear Envelope ◽

Muscle Weakness ◽

Congenital Muscular Dystrophy ◽

Envelope Proteins ◽

Accelerated Ageing ◽

Age Related ◽

Skeletal Muscle Weakness ◽

Genes Encoding

Abstract Skeletal muscle weakness is an important determinant of age-related declines in independence and quality of life but its causes remain unclear. Accelerated ageing syndromes such as Hutchinson–Gilford Progerin Syndrome, caused by mutations in genes encoding nuclear envelope proteins, have been extensively studied to aid our understanding of the normal biological ageing process. Like several other pathologies associated with genetic defects to nuclear envelope proteins including Emery–Dreifuss muscular dystrophy, Limb–Girdle muscular dystrophy and congenital muscular dystrophy, these disorders can lead to severe muscle dysfunction. Here, we first describe the structure and function of nuclear envelope proteins, and then review the mechanisms by which mutations in genes encoding nuclear envelope proteins induce premature ageing diseases and muscle pathologies. In doing so, we highlight the potential importance of such genes in processes leading to skeletal muscle weakness in old age.

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