Mutations in the LMNA gene, which encodes the nuclear envelope (NE) proteins lamins A/C, cause Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy and other diseases collectively known ...as laminopathies. The mechanisms responsible for these diseases remain incompletely understood. Using three mouse models of muscle laminopathies and muscle biopsies from individuals with LMNA-related muscular dystrophy, we found that Lmna mutations reduced nuclear stability and caused transient rupture of the NE in skeletal muscle cells, resulting in DNA damage, DNA damage response activation and reduced cell viability. NE and DNA damage resulted from nuclear migration during skeletal muscle maturation and correlated with disease severity in the mouse models. Reduction of cytoskeletal forces on the myonuclei prevented NE damage and rescued myofibre function and viability in Lmna mutant myofibres, indicating that myofibre dysfunction is the result of mechanically induced NE damage. Taken together, these findings implicate mechanically induced DNA damage as a pathogenic contributor to LMNA skeletal muscle diseases.
This table is published annually in the December issue. Its purpose is to provide the reader of Neuromuscular Disorders with an updated list of monogenic neuromuscular diseases due to a primary ...defect residing in the nuclear genome. It comprises diseases in which the causative gene is known or at least localized on a chromosome, if not yet identified. Diseases for which the locus has not been mapped or which are due to defects involving mitochondrial genes are not included.
LMNA mutations in patients are responsible for a dilated cardiomyopathy. Molecular mechanisms underlying the origin and development of the pathology are unknown. Herein, using mouse pluripotent ...embryonic stem cells (ESCs) and a mouse model both harboring the p.H222P Lmna mutation, we found early defects in cardiac differentiation of mutated ESCs and dilatation of mutated embryonic hearts at E13.5, pointing to a developmental origin of the disease. Using mouse ESCs, we demonstrated that cardiac differentiation of LmnaH222P/+ was impaired at the mesodermal stage. Expression of Mesp1, a mesodermal cardiogenic gene involved in epithelial-to-mesenchymal transition of epiblast cells, as well as Snai1 and Twist expression, was decreased in LmnaH222P/+ cells compared with WT cells in the course of differentiation. In turn, cardiomyocyte differentiation was impaired. ChIP assay of H3K4me1 in differentiating cells revealed a specific decrease of this histone mark on regulatory regions of Mesp1 and Twist in LmnaH222P/+ cells. Downregulation or inhibition of LSD1 that specifically demethylated H3K4me1 rescued the epigenetic landscape of mesodermal LmnaH222P/+ cells and in turn contraction of cardiomyocytes. Inhibition of LSD1 in pregnant mice or neonatal mice prevented cardiomyopathy in E13.5 LmnaH222P/H222P offspring and adults, respectively. Thus, LSD1 appeared to be a therapeutic target to prevent or cure dilated cardiomyopathy associated with a laminopathy.
Many imaging methods have been proposed to act as surrogate markers of organ damage, yet for many candidates the essential biomarkers characteristics of the injured organ have not yet been described. ...Hyperpolarized 1-13Cpyruvate allows real time monitoring of metabolism in vivo. ParaHydrogen Induced Polarization (PHIP) is a portable, cost effective technique able to generate 13C MR hyperpolarized molecules within seconds. The introduction of the Side Arm Hydrogenation (SAH) strategy offered a way to widen the field of PHIP generated systems and to make this approach competitive with the currently applied dissolution-DNP (Dynamic Nuclear Polarization) method. Herein, we describe the first in vivo metabolic imaging study using the PHIP-SAH hyperpolarized 1-13Cpyruvate. In vivo maps of pyruvate and of its metabolic product lactate have been acquired on a 1 T MRI scanner. By comparing pyruvate/lactate 13C label exchange rate in a mouse model of dilated cardiomyopathy, it has been found that the metabolic dysfunction occurring in the cardiac muscle of the diseased mice can be detected well before the disease can be assessed by echocardiographic investigations.
Human
encodes LAP1, a nuclear envelope protein expressed in most human tissues, which has been linked to various biological processes and human diseases. The clinical spectrum of diseases related to ...mutations in
is broad, including muscular dystrophy, congenital myasthenic syndrome, cardiomyopathy, and multisystemic disease with or without progeroid features. Although rare, these recessively inherited disorders often lead to early death or considerable functional impairment. Developing a better understanding of the roles of LAP1 and mutant
-associated phenotypes is paramount to allow therapeutic development. To facilitate further studies, this review provides an overview of the known interactions of LAP1 and summarizes the evidence for the function of this protein in human health. We then review the mutations in the
gene and the clinical and pathological characteristics of subjects with these mutations. Lastly, we discuss challenges to be addressed in the future.
Lamins A and C are intermediate filament nuclear envelope proteins encoded by the
gene. Mutations in
cause autosomal dominant severe heart disease, accounting for 10% of dilated cardiomyopathy (DCM). ...Characterised by progressive conduction system disease, arrhythmia and systolic impairment, lamin A/C heart disease is more malignant than other common DCMs due to high event rates even when the left ventricular impairment is mild. It has several phenotypic mimics, but overall it is likely to be an under-recognised cause of DCM. In certain clinical scenarios, particularly familial DCM with early conduction disease, the pretest probability of finding an
mutation may be quite high.Recognising lamin A/C heart disease is important because implantable cardioverter defibrillators need to be implanted early. Promising oral drug therapies are within reach thanks to research into the mitogen-activated protein kinase (MAPK) and affiliated pathways. Personalised heart failure therapy may soon become feasible for
, alongside personalised risk stratification, as variant-related differences in phenotype severity and clinical course are being steadily elucidated.Genotyping and family screening are clinically important both to confirm and to exclude
mutations, but it is the three-pronged integration of such genetic information with functional data from in vivo cardiomyocyte mechanics, and pathological data from microscopy of the nuclear envelope, that is properly reshaping our
knowledge base, one variant at a time. This review explains the biology of lamin A/C heart disease (genetics, structure and function of lamins), clinical presentation (diagnostic pointers, electrocardiographic and imaging features), aspects of screening and management, including current uncertainties, and future directions.
Mutations in the lamin A/C gene, LMNA, can cause dilated cardiomyopathy. We have shown abnormal activation of the extracellular signal-regulated kinase (ERK) and the c-jun N-terminal kinase (JNK) ...branches of the mitogen-activated protein kinase signaling cascade in hearts from Lmna(H222P/H222P) mice that develop dilated cardiomyopathy. We recently showed that partial inhibition of ERK and JNK signaling before the onset of cardiomyopathy in Lmna(H222P/H222P) mice prevented the development of left ventricle dilatation and decreased cardiac ejection fraction at a time when they occurred in untreated mice.
To determine whether pharmacological inhibitors of ERK and JNK signaling could be clinically useful to treat cardiomyopathy caused by LMNA mutation, we administered them to Lmna(H222P/H222P) mice after they developed left ventricular dilatation and decreased ejection fraction. Lmna(H222P/H222P) mice were treated with ERK and JNK signaling inhibitors from 16 to 20 or, in pilot experiments, 19 to 24 weeks of age. The inhibitors blocked increased expression of RNAs encoding natriuretic peptide precursors and proteins involved in sarcomere architecture that occurred in placebo-treated mice. Echocardiography and histological analysis demonstrated that treatment prevented left ventricular end-systolic dilatation, increased ejection fraction, and decreased myocardial fibrosis.
Inhibitors of ERK and JNK signaling could potentially be used to treat humans with cardiomyopathy caused by LMNA mutations.
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