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Nuclear Envelope and Muscular Dystrophy

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Nuclear Envelope and Muscular Dystrophy Nationwide Children’s Hospital August 25, 2015 Nuclear Envelope and Muscular Dystrophy Howard J. Worman, M.D. Columbia University Columbia University Medical Center The Nuclear Envelope By D. W. Fawcett The Nuclear Envelope: Nuclear Lamina Dauer & Worman, 2009 Nuclear Lamins: A Brief “Ancient” History Dwyer& Blobel (1975) Aebi et al. (1986) Aebi et al. (1986) Gerace, Blum & Blobel (1978) Goldman et al. (1986) McKeon et al. (1986) Fisher et al. (1986) HUMAN NUCLEAR LAMINS LOCUS CHROMOSOME PROTEINS CELL-TYPES EXPRESSED LMNA 1q21.2-21.3 Lamin A Differentiated Somatic Lamin C Differentiated Somatic Lamin A D10 Differentiated Somatic Lamin C2 Germ LMNB1 5q23.2-31.1 Lamin B1 Apparently All Somatic LMNB2 19p13.3 Lamin B2 All or Most Somatic Lamin B3 Germ LMNA Encoding A-type Lamins Lin and Worman, JBC, 1993 Localization to chromosome 1q21.2–q21.3 Wynder et al., Genomics, 1995 Mutations in LMNA Cause Diseases (“Laminopathies”) with Four Major Tissue-Selective Phenotypes Dauer and Worman Dev. Cell (2009) LMNA Genotype- Phenotype Correlations Dominant mutations causing muscle diseases are missense, splicing and small deletions and even haploinsufficiency Recessive missense mutation peripheral neuropathy Dominant mutations cluster in a small region encoded of exon 8 in partial lipodystrophy Recessive missense in MAD Dominant G608G or S608G in HGPF Worman and Courvalin (2005) Hutchinson-Gilford Progeria Syndrome (HGPS) Normally, lamin A starts as a precursor prelamin A, which is fanesylated. The farnesylated precursor is recognized by ZMPSTE24 endoprotease and cleaved; mature lamin A is not farnesylated. From Worman and Courvalin. (2005) farnesyl The LMNA mutation causing HGPS leads to expression of Paradisi et al. (2005) a truncated prelamin A (“progerin”), which remains farnesylated. Modified from Eriksson et al. Nature (2003) Evidence that Abnormal Farnesylation of Progerin is Involved in Pathogenesis of HGPS •Treatment of cultured fibroblasts from model mice and affected human with protein prenylation inhibitors reverse abnormal nuclear shape characteristic of cells expressing progerin •Treatment of mice with a targeted HGPS mutation with farnesyltransferase inhibitors improve phenotype •Based on above, clinical trials in affected children have been conducted but unfortunately uncontrolled ones •There are some LMNA mutations that cause progeroid phenotypes that apparently do not alter prenylation LMNA Mutations Causing Striated Muscle Disease Versus LMNA Mutations Causing Lipodystrophy Dunnigan-type Familial Partial Lipodystrphy Emery-Dreifuss Muscular Dystrophy and Variant Disorders The vast majority of LMNA mutations in Dunnigan-type partial lipodsytrophy change the surface charge of an Ig fold in the lamin A/C tail domain Cter Nter Cter Nter W520 Y481 R453 R527 R482 G465 V442, V452, I469, N456 I497, T528, L530 K486 Krimm et al. Stucture (2001) Recessive LMNA Mutations Charcot-Marie-Tooth type 2B1 Mandibuloacryl dysplasia Tazir et al. (2004) Novelli et al. (2002) LMNA R298C LMNA R2527H Integral Inner Nuclear Membrane Protein Gene Mutations EDM – emerin Emery-Dreifuss Muscular Dystrophy (X-linked) and variants LBR – lamin B receptor Pelger-Huët Anomaly (Heterozygous) HEM/Greenberg Skeletal Dysplasia (Homozygous) MAN1/LEMD3 Osteopoikilosis, Buschke-Ollendorff Syndrome Outer Nuclear Membrane Protein/Perinuclear Space Gene Mutations SYNE1 – nesprin-1 Autosomal Recessive Cerebellar Ataxia Arthrogryposis Myopathies SYNE2 – nesprin-2 Myopathies SYNE4 – nesprin-4 High Frequency Hearing Loss TOR1A – torsinA DYT1 Dystonia Gundersen and Worman Cell (2013) LMNA Cardiomypathy and Muscular Dystrophy LMNA Linked Myopathies Emery-Dreifuss Limb-girdle Type 1B Dilated Cardiomyopathy 1A All three clinical phenotypes can occur in members of the same family with the same mutation and there is overlap between phenotypes: LMNA dilated cardiomyopathy with variable skeletal muscle involvement. LMNA Cardiomyopathy •Approximately 6% to 9% of all dilated cardiomyopathies •Up to 30% of dilated cardiomyopathies with AV block and skeletal muscle involvement van Berlo et al. J. Mol. Med. 2004; 83:79-83 Taylor et al. J. Am. Coll. Cardiol. 2003;41: 771-780 LMNAH222P/H222P Mouse Model of Emery-Dreifuss Muscular Dystrophy (Arimura et al. 2005) Heart disease progression from 8 to 20 weeks of age in male mice Heart structure and function Significant LV dilatation and decreased fractional shortening by echocardiography Abnormal Signaling in Hearts of LmnaH222P/H222 Mice HEART at 10 weeks AFFYMETRIX 430 2.0 MAP Kinase AKT/mTOR Early Activation of ERK1/2 in Hearts of LmnaH222P/H222P Mice > ERK1/2 and downstream genes are abnormally activated prior to (4 weeks and 7 weeks) and concurrent with (10 weeks) the onset of cardiomyopathy in hearts of LmnaH222P/H222P mice 4 weeks Choi et al. Sci Transl Med 2012 Muchir et al. J Clin Invest 2007 MEK1/2 MEK1/2 Inhibitor Protocol P ERK PD98059 Selumetinib P CIP-137401 Drug Administration ERK 1 6 w e e k s 2 0 w e e k s E n d p o i n t s -Echocardiography -Biochemical Markers -Cardiac Fibrosis MEK 1 / 2 I n h i b i t o r T r e a t m e n t Target Inhibition – decreased phosphorylated ERK1/2 (pERK1/2) in heart after selumetinib treatment MEK 1 / 2 I n h i b i t o r T r e a t m e n t Muchir et al. 2012 MEK 1 / 2 I n h i b i t o r T r e a t m e n t Fibrosis – decreased fibrosis tissue and collagen gene expression 20% 12% MEK 1 / 2 INHIBITION Survival – prolonged median survival (proprietary MEK1/2 inhibitor) MEK1/2 Inhibitor Treatment Blocks AKT/mTOR in Hearts of LmnaH222P/H222P Mice Chhoi et al. Sci Transl Med (2012) Increased AKT/mTOR Activity Correlates with Decreased Autophagy Lmna Mice Human Subjects Chhoi et al. Sci Transl Med (2012) Temsirolimus Blocks mTOR Activity Improving Heart Function and Enhancing Autophagy Chhoi et al. Sci Transl Med (2012) One Model of LMNA Cardiomyopathy Normal Heart Outstanding Theoretical Question: Outstanding Practical Question: How do LMNA mutation Can use of these drugs be CIP-137401 activate these pathways? optimized to treat human subjects? Dilated Heart Emerin and LAP1 and Muscular Dystrophy Mutations in EMD Encoding Emerin Phenocopy Myopathies Caused by LMNA Mutations X-linked Emery-Dreifuss Muscular Dystrophy (and related myopathies) Emerin binds to A-type lamins In most cases, emerin is lacking from the nuclear envelope Muscle Frozen Sections Anti-emerin Ab Normal X-EDMD X-EDMD Nagano et al. Nat Genet. 1996;12:254-259 Modified from A.E.H. Emery Emerin as a Candidate LAP1 Binding Protein Lamina-associated polypeptide 1 (LAP1) integral inner nuclear membrane protein of unclear function In an unbiased proteomics screen for interacting proteins in collaboration with Bill Dauer, emerin was found to be top candidate Emerin Binds to LAP1 Biochemical Assays FRET Shin et al. Dev Cell (2013) Loss of Emerin: of Mice and Men Pacemaker Apparently Normal Mouse Melcon et al. Hum Mol Genet 2006;15:637-651 Emery-Dreifuss Muscular Ozawa et al. Am J Pathol 2006;168:907-917 Dystrophy A.E. H. Emery (2000) Why Don’t Emerin Null Mice Get Sick? Mouse skeletal muscle has diminished emerin compared to human. Conversely, LAP1 is significantly higher in mouse than human striated muscle. Shin et al. Dev Cell (2013) Therefore, We Depleted LAP1 from Mouse Skeletal Muscle Shin et al. Dev Cell (2013) Mice Lacking LAP1 in Skeletal Muscle Shin et al. Dev Cell (2013) LAP1 Depletion Causes Muscular Dystrophy Shin et al. Dev Cell (2013) Depletion of LAP1 Striated Muscle on Emerin Null Background Shin et al. Dev Cell (2013) Control: Deplete LAP1 from Hepatocytes Shin et al. Dev Cell (2013) Deplete LAP1 from Hepatocytes – Minimal Pathology Shin et al. Dev Cell (2013) Depletion of LAP1 from Heart Shin et al. Nucleus (2014) Depletion of LAP1 from Heart Decreases Left Ventricular Fractional Shortening Shin et al. Nucleus (2014) Disruption of Emerin-Lamin A/C-LAP1 Complex: Cardiomyoapthy and Muscular Dystrophy Disruption Emerin-Lamin A/C-LAP1 Complex ERK1/2 and AKT/mTOR Striated Muscle Disease Columbia Past & Present Collaborators Elsewhere Revekka Boguslavsky Takuro Arimura Jason Choi Gisèle Bonne Gregg Gundersen Jean-Claude Courvalin Alan Herron Bill Dauer Stephen Lehnart Yukiko Hayashi Caroline LeDour Feng Lin Micheline Paulin-Levasseur Angelika Lüdtke Sophie Zinn-Justin Ivan Méndez-López Antoine Muchir Cecilia Östlund Paul Pavlides Jian Shan Ji-Yeon Shin Bruno Soullam Yuexia Wang Wei Wu Quan Ye Funding BioAccelerate NYC Prize Los Angeles Thoracic and Cardiovascular Foundation .
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