Mutations in Smooth Muscle Alpha-Actin (ACTA2) Cause Coronary Artery Disease, Stroke, and Moyamoya Disease, Along with Thoracic Aortic Disease Dong-Chuan.

Slides:

Advertisements

Similar presentations

Functional Analysis of the Neurofibromatosis Type 2 Protein by Means of Disease- Causing Point Mutations Renee P. Stokowski, David R. Cox The American.

Advertisements

Diffuse Type Gastric and Lobular Breast Carcinoma in a Familial Gastric Cancer Patient with an E-Cadherin Germline Mutation Gisela Keller, Holger Vogelsang,

Volume 144, Issue 1, Pages 7-14 (May 1999)

Mutation in NSUN2, which Encodes an RNA Methyltransferase, Causes Autosomal- Recessive Intellectual Disability Muzammil Ahmad Khan, Muhammad Arshad Rafiq,

Rapid Molecular Analysis of the STAT3 Gene in Job Syndrome of Hyper-IgE and Recurrent Infectious Diseases Attila Kumánovics, Carl T. Wittwer, Robert.

Endothelial to Mesenchymal Transition Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension Robert B. Good, Adrian J. Gilbane, Sarah.

Chronic Infantile Neurological Cutaneous and Articular Syndrome Is Caused by Mutations in CIAS1, a Gene Highly Expressed in Polymorphonuclear Cells and.

Mutations in AGBL1 Cause Dominant Late-Onset Fuchs Corneal Dystrophy and Alter Protein-Protein Interaction with TCF4 S. Amer Riazuddin, Shivakumar Vasanth,

Transglutaminase type 2 in human abdominal aortic aneurysm is a potential factor in the stabilization of extracellular matrix Sung Shin, MD, Yong-Pil.

Mutations in the Beta Propeller WDR72 Cause Autosomal-Recessive Hypomaturation Amelogenesis Imperfecta Walid El-Sayed, David A. Parry, Roger C. Shore,

Li Wang, Dong-chuan Guo, Jiumei Cao, Limin Gong, Kristine E

LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections Dong-chuan Guo, Ellen S. Regalado, Amelie Pinard, Jiyuan.

A Truncating Mutation of CEP135 Causes Primary Microcephaly and Disturbed Centrosomal Function Muhammad Sajid Hussain, Shahid Mahmood Baig, Sascha Neumann,

Targeted High-Throughput Sequencing Identifies Mutations in atlastin-1 as a Cause of Hereditary Sensory Neuropathy Type I Christian Guelly, Peng-Peng.

TBC1D24, an ARF6-Interacting Protein, Is Mutated in Familial Infantile Myoclonic Epilepsy Antonio Falace, Fabia Filipello, Veronica La Padula, Nicola.

ADAMTS7 Cleavage and Vascular Smooth Muscle Cell Migration Is Affected by a Coronary-Artery-Disease-Associated Variant Xiangyuan Pu, Qingzhong Xiao,

Molecular Regulation of UVB-Induced Cutaneous Angiogenesis

Diana C. Blaydon, Sarah L. Etheridge, Janet M

Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest Yao Xu, Yingli Shi, Jing Fu, Min Yu, Ruizhi Feng, Qing Sang, Bo Liang,

A New Lamin A Mutation Associated with Acrogeria Syndrome

Ali Sazci, Ph. D. , Nesrin Ercelen, M. D. , Emel Ergul, M. S

Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus Na Li, Lakshman Subrahmanyan, Emily Smith,

Volume 17, Issue 1, Pages (January 2010)

Peter Ianakiev, Michael W

GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism

Haplotype-Sharing Analysis Implicates Chromosome 7q36 Harboring DPP6 in Familial Idiopathic Ventricular Fibrillation Marielle Alders, Tamara T. Koopmann,

Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms,

Novel SLC39A4 Mutations in Acrodermatitis Enteropathica

Genotype/Phenotype Analysis of a Photoreceptor-Specific ATP-Binding Cassette Transporter Gene, ABCR, in Stargardt Disease Richard Alan Lewis, Noah F.

A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility Tailai Chen, Yuehong Bian, Xiaoman Liu, Shigang Zhao, Keliang.

Comparison of cell-type-specific vs transmural aortic gene expression in experimental aneurysms Eiketsu Sho, MD, PhD, Mien Sho, MD, Hiroshi Nanjo, MD,

Dong-chuan Guo, Megan L. Grove, Siddharth K

Tristan F. W. McMullan, Andrew R. Collins, Anthony G. Tyers, David O

High Incidence of Later-Onset Fabry Disease Revealed by Newborn Screening* Marco Spada, Severo Pagliardini, Makiko Yasuda, Turgut Tukel, Geetha Thiagarajan,

Mutation of Solute Carrier SLC16A12 Associates with a Syndrome Combining Juvenile Cataract with Microcornea and Renal Glucosuria Barbara Kloeckener-Gruissem,

The Case ∣ A young man with acute kidney injury after exercise

Volume 17, Issue 1, Pages (January 2010)

Compound Heterozygous TGM1 Mutations Including a Novel Missense Mutation L204Q in a Mild Form of Lamellar Ichthyosis Masashi Akiyama, Itsuro Matsuo

Aortic wall cell proliferation via basic fibroblast growth factor gene transfer limits progression of experimental abdominal aortic aneurysm Katsuyuki.

A Missense Mutation in the Zinc-Finger Domain of the Human Hairless Gene Underlies Congenital Atrichia in a Family of Irish Travellers Wasim Ahmad, Alan.

Homozygous Mutations in WEE2 Cause Fertilization Failure and Female Infertility Qing Sang, Bin Li, Yanping Kuang, Xueqian Wang, Zhihua Zhang, Biaobang.

Identification of a Kir3.4 Mutation in Congenital Long QT Syndrome

Characterization of the inflammatory and apoptotic cells in the aortas of patients with ascending thoracic aortic aneurysms and dissections Rumin He,

Bilineal Disease and Trans-Heterozygotes in Autosomal Dominant Polycystic Kidney Disease York Pei, Andrew D. Paterson, Kai Rong Wang, Ning He, Donna.

TBC1D24, an ARF6-Interacting Protein, Is Mutated in Familial Infantile Myoclonic Epilepsy Antonio Falace, Fabia Filipello, Veronica La Padula, Nicola.

Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang,

Carotid plaque instability and ischemic symptoms are linked to immaturity of microvessels within plaques Benjamin J. Dunmore, PhD, Mark J. McCarthy,

Next-Generation Sequencing Identifies Mutations of SMPX, which Encodes the Small Muscle Protein, X-Linked, as a Cause of Progressive Hearing Impairment

Lack of EVER2 Protein in Two Epidermodysplasia Verruciformis Patients with Skin Cancer Presenting Previously Unreported Homozygous Genetic Deletions in.

In vitro differences between smooth muscle cells derived from varicose veins and normal veins Ying Xiao, PhD, Zhibin Huang, MD, Henghui Yin, PhD, Ying.

A Novel Dominant Mutation in Plakoglobin Causes Arrhythmogenic Right Ventricular Cardiomyopathy Angeliki Asimaki, Petros Syrris, Thomas Wichter, Paul.

Dominique J. Verlaan, Adrian M. Siegel, Guy A. Rouleau

Jack Heath, Abigail K. Langton, Nigel L. Hammond, Paul A

Recurrence of the T666M Calcium Channel CACNA1A Gene Mutation in Familial Hemiplegic Migraine with Progressive Cerebellar Ataxia A. Ducros, C. Denier,

James Gailit, Mary J. Marchese, Richard R. Kew, Barry L. Gruber

A Unique Point Mutation in the PMP22 Gene Is Associated with Charcot-Marie-Tooth Disease and Deafness Margaret J. Kovach, Jing-Ping Lin, Simeon Boyadjiev,

Immunosuppressive treatment of aortic allografts

Molecular and Clinical Study of 18 Families with ADCA Type II: Evidence for Genetic Heterogeneity and De Novo Mutation P. Giunti, G. Stevanin, P.F. Worth,

KLOTHO Allele Status and the Risk of Early-Onset Occult Coronary Artery Disease Dan E. Arking, Diane M. Becker, Lisa R. Yanek, Daniele Fallin, Daniel.

Atteeq U. Rehman, Regie Lyn P. Santos-Cortez, Robert J

Oligodontia Is Caused by Mutation in LTBP3, the Gene Encoding Latent TGF-β Binding Protein 3 Abdul Noor, Christian Windpassinger, Irina Vitcu, Marija.

Early Onset of Severe Familial Amyotrophic Lateral Sclerosis with a SOD-1 Mutation: Potential Impact of CNTF as a Candidate Modifier Gene Ralf Giess,

Effect of Vein Graft Harvesting on Endothelial Nitric Oxide Synthase and Nitric Oxide Production Michael R. Dashwood, PhD, Kay Savage, PhD, Audrey Dooley,

Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease Dong-chuan Guo, Xue-Yan Duan, Ellen.

Mutations in CHEK2 Associated with Prostate Cancer Risk

Giovanni Parmigiani, Donald A. Berry, Omar Aguilar

The Angiogenesis Inhibitor Vasostatin does not Impair Wound Healing at Tumor- Inhibiting Doses Bernhard Lange-Asschenfeldt, Paula Velasco, Michael Streit,

Mutations in NEXN, a Z-Disc Gene, Are Associated with Hypertrophic Cardiomyopathy Hu Wang, Zhaohui Li, Jizheng Wang, Kai Sun, Qiqiong Cui, Lei Song, Yubao.

Gain-of-Function Mutation of KIT Ligand on Melanin Synthesis Causes Familial Progressive Hyperpigmentation Zhi-Qiang Wang, Lizhen Si, Quan Tang, Debao.

Mutations in PDGFRB Cause Autosomal-Dominant Infantile Myofibromatosis

Presentation transcript:

Mutations in Smooth Muscle Alpha-Actin (ACTA2) Cause Coronary Artery Disease, Stroke, and Moyamoya Disease, Along with Thoracic Aortic Disease Dong-Chuan Guo, Christina L. Papke, Van Tran-Fadulu, Ellen S. Regalado, Nili Avidan, Ralph Jay Johnson, Dong H. Kim, Hariyadarshi Pannu, Marcia C. Willing, Elizabeth Sparks, Reed E. Pyeritz, Michael N. Singh, Ronald L. Dalman, James C. Grotta, Ali J. Marian, Eric A. Boerwinkle, Lorraine Q. Frazier, Scott A. LeMaire, Joseph S. Coselli, Anthony L. Estrera, Hazim J. Safi, Sudha Veeraraghavan, Donna M. Muzny, David A. Wheeler, James T. Willerson, Robert K. Yu, Sanjay S. Shete, Steven E. Scherer, C.S. Raman, L. Maximilian Buja, Dianna M. Milewicz The American Journal of Human Genetics Volume 84, Issue 5, Pages 617-627 (May 2009) DOI: 10.1016/j.ajhg.2009.04.007 Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 1 Vascular Diseases in Families with ACTA2 Mutations (A) Pedigrees of 12 families with ACTA2 mutations in which the mutation segregates with a number of vascular diseases, including TAAD, premature onset of CAD, and stroke. The disease and mutation status of individuals are as indicated in the figure legend. (B) Three families with ACTA2 R258 mutations with early age at onset of stroke and MMD. (C) Pedigrees of patients with ACTA2 mutations identified from Texgen cohort. Pedigrees of two patients with nonfamilial TAAD and de novo ACTA2 mutations and of one patient with nonfamilial TAAD, a sister with MMD, and a mother with premature CAD due to an ACTA2 mutation. Numbers and letters under each circle or square in the pedigree represent the following: the first line shows the individual ID number; the second line shows age at onset of the vascular disease(s), which is color coded based on the vascular disease (see the figure legend); and an asterisk next to a symbol indicates that individuals had MMD. Individuals in (C) are labeled with their sample ID number. Circles represent females, and squares represent males. A slash through a circle or square indicates a deceased person. A pound sign (#) indicates an individual who may have carried the ACTA2 mutation, on the basis of their location in the pedigree, but was not assumed to harbor a mutation in the genetic and clinical analysis of ACTA2-mutation carriers. The American Journal of Human Genetics 2009 84, 617-627DOI: (10.1016/j.ajhg.2009.04.007) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 2 Genotype-Phenotype Correlation between Location of Mutation and Vascular Diseases (A) Location of all ACTA2 mutations and the specific phenotypes observed in patients heterozygous for those mutations. The mutations are listed in sequential order and align with the exon in which they are located. “No.” indicates the number of identified individuals who carry each specific mutation. The headings TAAD, Stroke, and CAD denote the number of individuals affected by each of these conditions. An asterisk indicates a mutation leading to the onset of ischemic strokes prior to the age of 20 years. (B) The ribbon diagram of SM α-actin, identifying the location of the different mutations at the protein-structure level. The recurrent ACTA2 mutation leading to ischemic strokes at a young age (p.R258C/H, shown in green) lies within subdomain 4, whereas mutations occurring in multiple individuals and leading primarily to premature CAD (p.R149C and p.R118Q, shown in red) all lie within the hydrophobic cleft. The American Journal of Human Genetics 2009 84, 617-627DOI: (10.1016/j.ajhg.2009.04.007) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 3 ACTA2 Mutations Lead to Increased SMC and Myofibroblast Proliferation in Culture (A) Coronary artery from 28-year-old TAA441:IV:4, stained with Movat's stain and SM α-actin antibody. The coronary artery showed 70% narrowing of the vessel due to a fibrocellular atherosclerotic plaque (top two panels; magnification 40×; scale bar represents 1.0 mm). Higher magnification (200×; scale bar represents 200 μm) revealed that these cells contain SM α-actin. (B) The epicardial arteries from a 50-year-old man, TAA441:III:7, and a 53-year-old woman, TAA015:III:1. H&E, Movat, and α-actin immunostaining of the tissue showed thickened vessels within the myocardium (magnification 200×; scale bar represents 200 μm). (C) Cell-proliferation assays (BrdU incorporation) illustrate that SMCs explanted from patients heterozygous for an ACTA2 mutation (n = 2) proliferate more rapidly than matched control SMCs (n = 2). (D) Myofibroblasts (fibroblasts exposed to TGF-β1 for 72 hr) from patients heterozygous for ACTA2 mutations (n = 9) proliferate more rapidly than matched controls (n = 10). Data are expressed as means ± SEM, and p values are indicated. Immunoblotting for SM α-actin from the cell lysates confirms that TGF-β1 exposure increased cellular SM α-actin. The American Journal of Human Genetics 2009 84, 617-627DOI: (10.1016/j.ajhg.2009.04.007) Copyright © 2009 The American Society of Human Genetics Terms and Conditions