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Cristina Guillín-Amarelle, Antía Fernández-Pombo, Sofía Sánchez-Iglesias, David Araújo-Vilar
The nuclear lamina is a complex reticular structure that covers the inner face of the nucleus membrane in metazoan cells. It is mainly formed by intermediate filaments called lamins, and exerts essential functions to maintain the cellular viability. Lamin A/C provides mechanical steadiness to the nucleus and regulates genetic machinery. Laminopathies are tissue-specific or systemic disorders caused by variants in LMNA gene (primary laminopathies) or in other genes encoding proteins which are playing some role in prelamin A maturation or in lamin A/C function (secondary laminopathies)...
March 20, 2018: Nucleus
Ryszard Rzepecki, Yosef Gruenbaum
Lamins are evolutionarily conserved nuclear intermediate filament proteins. They provide structural support for the nucleus and help regulate many other nuclear activities. Mutations in human lamin genes, and especially in the LMNA gene, cause numerous diseases, termed laminopathies, including muscle, cardiac, metabolic, neuronal and early aging diseases. Most laminopathies arise from autosomal dominant missense mutations. Many of the mutant residues are conserved in the lamin genes of the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster...
March 20, 2018: Nucleus
Sarah Chiang, Paolo Cotzia, David M Hyman, Alexander Drilon, William D Tap, Lei Zhang, Jaclyn F Hechtman, Denise Frosina, Achim A Jungbluth, Rajmohan Murali, Kay J Park, Robert A Soslow, Esther Oliva, A John Iafrate, Ryma Benayed, Marc Ladanyi, Cristina R Antonescu
Tropomyosin receptor kinase (Trk) inhibitors have shown high response rates in patients with tumors harboring NTRK fusions. We identified 4 NTRK fusion-positive uterine sarcomas that should be distinguished from leiomyosarcoma and undifferentiated uterine sarcoma. NTRK rearrangements were detected by fluorescence in situ hybridization (FISH) and/or targeted RNA or DNA sequencing in 4 undifferentiated uterine sarcomas with spindle cell morphology. Because of histologic overlap with leiomyosarcoma, TrkA and pan-Trk immunohistochemistry was performed in 97 uterine leiomyosarcomas...
March 16, 2018: American Journal of Surgical Pathology
Graham F Brady, Raymond Kwan, Juliana Bragazzi Cunha, Jared S Elenbaas, M Bishr Omary
The nuclear lamina is a multi-protein lattice composed of A- and B-type lamins and their associated proteins. This protein lattice associates with heterochromatin and integral inner nuclear membrane proteins, providing a link between the genome, nucleoskeleton, and cytoskeleton. In the 1990s, mutations in EMD and LMNA were linked to Emery-Dreifuss muscular dystrophy. Since then, the number of diseases attributed to nuclear lamina defects, including laminopathies and other disorders, has increased to include more than 20 distinct genetic syndromes...
March 13, 2018: Gastroenterology
Feriel Azibani, Astrid Brull, Ludovic Arandel, Maud Beuvin, Isabelle Nelson, Arnaud Jollet, Esma Ziat, Bernard Prudhon, Sofia Benkhelifa-Ziyyat, Marc Bitoun, Stéphanie Lorain, Gisèle Bonne, Anne T Bertrand
We assessed the potential of Lmna-mRNA repair by spliceosome-mediated RNA trans-splicing as a therapeutic approach for LMNA-related congenital muscular dystrophy. This gene therapy strategy leads to reduction of mutated transcript expression for the benefit of corresponding wild-type (WT) transcripts. We developed 5'-RNA pre-trans-splicing molecules containing the first five exons of Lmna and targeting intron 5 of Lmna pre-mRNA. Among nine pre-trans-splicing molecules, differing in the targeted sequence in intron 5 and tested in C2C12 myoblasts, three induced trans-splicing events on endogenous Lmna mRNA and confirmed at protein level...
March 2, 2018: Molecular Therapy. Nucleic Acids
C M Mak, S Pl Chen, N S Mok, W K Siu, H Hc Lee, C K Ching, P T Tsui, N C Fong, Y P Yuen, W T Poon, C Y Law, Y K Chong, Y W Chan, T C Yung, K Yy Fan, C W Lam
INTRODUCTION: Hereditary channelopathies and cardiomyopathies are potentially lethal and are clinically and genetically heterogeneous, involving at least 90 genes. Genetic testing can provide an accurate diagnosis, guide treatment, and enable cascade screening. The genetic basis among the Hong Kong Chinese population is largely unknown. We aimed to report on 28 unrelated patients with positive genetic findings detected from January 2006 to December 2015. METHODS: Sanger sequencing was performed for 28 unrelated patients with a clinical diagnosis of channelopathies or cardiomyopathies, testing for the following genes: KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A, for long QT syndrome; SCN5A for Brugada syndrome; RYR2 for catecholaminergic polymorphic ventricular tachycardia; MYH7 and MYBPC3 for hypertrophic cardiomyopathy; LMNA for dilated cardiomyopathy; and PKP2 and DSP for arrhythmogenic right ventricular dysplasia/cardiomyopathy...
March 2, 2018: Hong Kong Medical Journal, Xianggang Yi Xue za Zhi
Zeming Wu, Weiqi Zhang, Moshi Song, Wei Wang, Gang Wei, Wei Li, Jinghui Lei, Yu Huang, Yanmei Sang, Piu Chan, Chang Chen, Jing Qu, Keiichiro Suzuki, Juan Carlos Izpisua Belmonte, Guang-Hui Liu
Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively...
February 23, 2018: Protein & Cell
Nolwenn Briand, Anne-Claire Guénantin, Dorota Jeziorowska, Akshay Shah, Matthieu Mantecon, Emilie Capel, Marie Garcia, Anja Oldenburg, Jonas Paulsen, Jean-Sebastien Hulot, Corinne Vigouroux, Philippe Collas
The p.R482W hotspot mutation in A-type nuclear lamins causes familial partial lipodystrophy of Dunnigan-type (FPLD2), a lipodystrophic syndrome complicated by early-onset atherosclerosis. Molecular mechanisms underlying endothelial cell dysfunction conferred by the lamin A mutation remain elusive. However, lamin A regulates epigenetic developmental pathways and mutations could perturb these functions. Here, we demonstrate that lamin A R482W elicits endothelial differentiation defects in a developmental model of FPLD2...
February 9, 2018: Human Molecular Genetics
Erik Laurini, Valentina Martinelli, Thomas Lanzicher, Luca Puzzi, Daniele Borin, Suet Nee Chen, Carlin S Long, Patrice Lee, Luisa Mestroni, Matthew R G Taylor, Orfeo Sbaizero, Sabrina Pricl
Aims: Given the clinical impact of LMNA cardiomyopathies, understanding lamin function will fulfill a clinical need and will lead to advancement in the treatment of heart failure. A multidisciplinary approach combining cell biology, atomic force microscopy (AFM) and molecular modeling was used to analyze the biomechanical properties of human lamin A/C gene (LMNA) mutations (E161K, D192G, N195K) using an in vitro neonatal rat ventricular myocyte (NRVM) model. Methods and Results: The severity of biomechanical defects due to the three LMNA mutations correlated with the severity of the clinical phenotype...
February 8, 2018: Cardiovascular Research
Natalia von Muhlinen, Izumi Horikawa, Fatima Alam, Kazunobu Isogaya, Delphine Lissa, Borek Vojtesek, David P Lane, Curtis C Harris
Cellular senescence is a hallmark of normal aging and aging-related syndromes, including the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS), a rare genetic disorder caused by a single mutation in the LMNA gene that results in the constitutive expression of a truncated splicing mutant of lamin A known as progerin. Progerin accumulation leads to increased cellular stresses including unrepaired DNA damage, activation of the p53 signaling pathway and accelerated senescence. We previously established that the p53 isoforms ∆133p53 and p53β regulate senescence in normal human cells...
February 12, 2018: Oncogene
Beata Aleksiūnienė, Egle Preiksaitiene, Aušra Morkūnienė, Laima Ambrozaitytė, Algirdas Utkus
Many studies have shown that molecular karyotyping is an effective diagnostic tool in individuals with developmental delay/intellectual disability. We report on a de novo interstitial 1q22q23.1 microdeletion, 1.6 Mb in size, detected in a patient with short stature, microcephaly, hypoplastic corpus callosum, cleft palate, minor facial anomalies, congenital heart defect, camptodactyly of the 4-5th fingers, and intellectual disability. Chromosomal microarray analysis revealed a 1.6-Mb deletion in the 1q22q23...
February 9, 2018: Cytogenetic and Genome Research
Aurora Paola Borroni, Andrea Emanuelli, Pooja Anil Shah, Nataša Ilić, Liat Apel-Sarid, Biagio Paolini, Dhanoop Manikoth Ayyathan, Praveen Koganti, Gal Levy-Cohen, Michael Blank
A-lamins, encoded by the LMNA gene, are major structural components of the nuclear lamina coordinating essential cellular processes. Mutations in the LMNA gene and/or alterations in its expression levels have been linked to a distinct subset of human disorders, collectively known as laminopathies, and to cancer. Mechanisms regulating A-lamins are mostly obscure. Here, we identified E3 ubiquitin ligase Smurf2 as a physiological regulator of lamin A and its disease-associated mutant form progerin (LAΔ50), whose expression underlies the development of Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging syndrome...
February 5, 2018: Aging Cell
Jau-Ye Shiu, Lina Aires, Zhe Lin, Viola Vogel
A robust nanopillar platform with increased spatial resolution reveals that perinuclear forces, originating from stress fibres spanning the nucleus of fibroblasts, are significantly higher on these nanostructured substrates than the forces acting on peripheral adhesions. Many perinuclear adhesions embrace several nanopillars at once, pulling them into β1-integrin- and zyxin-rich clusters, which are able to translocate in the direction of cell motion without losing their tensile strength. The high perinuclear forces are greatly reduced upon inhibition of cell contractility or actin polymerization and disruption of the actin cap by KASH dominant-negative mutant expression...
February 5, 2018: Nature Cell Biology
Takashige Tobita, Seitaro Nomura, Takanori Fujita, Hiroyuki Morita, Yoshihiro Asano, Kenji Onoue, Masamichi Ito, Yasushi Imai, Atsushi Suzuki, Toshiyuki Ko, Masahiro Satoh, Kanna Fujita, Atsuhiko T Naito, Yoshiyuki Furutani, Haruhiro Toko, Mutsuo Harada, Eisuke Amiya, Masaru Hatano, Eiki Takimoto, Tsuyoshi Shiga, Toshio Nakanishi, Yasushi Sakata, Minoru Ono, Yoshihiko Saito, Seiji Takashima, Nobuhisa Hagiwara, Hiroyuki Aburatani, Issei Komuro
Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically heterogeneous. Cardiac function is improved after treatment in some cardiomyopathy patients, but little is known about genetic predictors of long-term outcomes and myocardial recovery following medical treatment. To elucidate the genetic basis of cardiomyopathy in Japan and the genotypes involved in prognosis and left ventricular reverse remodeling (LVRR), we performed targeted sequencing on 120 DCM (70 sporadic and 50 familial) and 52 HCM (15 sporadic and 37 familial) patients and integrated their genotypes with clinical phenotypes...
January 31, 2018: Scientific Reports
Pamela A Long, Jared M Evans, Timothy M Olson
Dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. DCM typically remains clinically silent until adulthood, yet symptomatic disease can develop in childhood. We sought to identify the genetic basis of pediatric DCM in 15 sporadic and three affected-siblings cases, comprised of 21 affected children (mean age, five years) whose parents had normal echocardiograms (mean age, 39 years). Twelve underwent cardiac transplantation and five died with severe heart failure...
August 8, 2017: Journal of Cardiovascular Development and Disease
Jared S Elenbaas, Juliana Bragazzi Cunha, Rodrigo Azuero-Dajud, Bradley Nelson, Elif A Oral, John A Williams, Colin L Stewart, M Bishr Omary
Lamins have important roles in nuclear structure and cell signaling. Several diseases are associated with mutations in the lamin A/C gene (LMNA in humans). Patients with familial partial lipodystrophy caused by LMNA mutations develop pancreatitis, but it is not clear how these mutations affect pancreatic function. We generated mice with inducible exocrine pancreas-specific disruption of Lmna and showed that LMNA is lost from most exocrine pancreas cells. LMNA-knockout pancreata develop endoplasmic reticulum stress with loss of acinar cell markers, increased autophagy, apoptosis, and cell proliferation, compared to CreERT2- mice (littermate controls)...
January 20, 2018: Gastroenterology
Kumi Fujita, Kazuhiro Hatta
We had encountered the case of membranous glomerulonephritis (MGN) with dilated cardiomyopathy due to LMNA gene mutation. LMNA mutation was known as a cause of 'laminopathy' such as dilated cardiomyopathy, muscular dystrophy, neuropathy and so on. LMNA gene might be a candidate of genetic basis in cryptogenic MGN.
January 18, 2018: CEN Case Reports
Gaelle Auguste, Priyatansh Gurha, Raffaella Lombardi, Cristian Coarfa, James T Willerson, Ali J Marian
RATIONALE: Mutations in the LMNA gene, encoding nuclear inner membrane protein lamin A/C, cause distinct phenotypes, collectively referred to as laminopathies. Heart failure, conduction defects, and arrhythmias are the common causes of death in laminopathies. OBJECTIVE: The objective of this study was to identify and therapeutically target the responsible mechanism(s) for cardiac phenotype in laminopathies. METHODS AND RESULTS: Whole-heart RNA sequencing was performed before the onset of cardiac dysfunction in the Lmna -/- and matched control mice...
March 2, 2018: Circulation Research
Raquel Toribio-Fernández, Virginia Zorita, Vera Rocha-Perugini, Salvador Iborra, Gloria Martínez Del Hoyo, Raphael Chevre, Beatriz Dorado, David Sancho, Francisco Sanchez-Madrid, Vicente Andrés, Jose-Maria Gonzalez-Granado
Differentiation of naive CD4+ T-cells into functionally distinct T helper (Th) subsets is critical to immunity against pathogen infection. Little is known about the role of signals emanating from the nuclear envelope for T-cell differentiation. The nuclear envelope protein lamin A/C is induced in naive CD4+ T-cells upon antigen recognition and acts as a link between the nucleus and the plasma membrane during T-cell activation. Here we demonstrate that the absence of lamin A/C in naive T-cell reduces Th1 differentiation without affecting Th2 differentiation in vitro and in vivo...
January 8, 2018: Cell Death & Disease
Lennart J de Vries, Mihran Martirosyan, Ron T van Domburg, Sip A Wijchers, Tamas Géczy, Tamas Szili-Torok
PURPOSE: Coupling interval (CI) variability of premature ventricular contractions (PVCs) is influenced by the underlying arrhythmia mechanism. The aim of this study was to compare CI variability of PVCs in different myocardial disease entities, in order to gain insight into their arrhythmia mechanism. METHODS: Sixty-four patients with four underlying pathologies were included: idiopathic (n = 16), non-ischemic dilated cardiomyopathy (NIDCM) (n = 16), familial cardiomyopathy (PLN/LMNA) (n = 16), and post-MI (n = 16)-associated PVCs...
January 5, 2018: Journal of Interventional Cardiac Electrophysiology: An International Journal of Arrhythmias and Pacing
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