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      Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?

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      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 3 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 14 , 40 , 41 , 42 , 27 , 43 , 1 , 2 ,
      Orphanet Journal of Rare Diseases
      BioMed Central
      Schimke immuno-osseous dysplasia, SMARCAL1, Elastin, Vascular disease, Pulmonary emphysema

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          Abstract

          Background

          Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown.

          Methods

          We reviewed the records of 65 patients with SMARCAL1 mutations. Molecular and immunohistochemical analyses were conducted on autopsy tissue from 4 SIOD patients.

          Results

          Thirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema. The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces. Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression.

          Conclusions

          This first comprehensive study of the vascular and pulmonary complications of SIOD shows that these commonly cause morbidity and mortality and might arise from impaired elastogenesis. Additionally, the effect of SMARCAL1 deficiency on elastin expression provides a model for understanding other features of SIOD.

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          Most cited references51

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          Supravalvular aortic stenosis.

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            Genetic diseases of connective tissues: cellular and extracellular effects of ECM mutations.

            Tissue-specific extracellular matrices (ECMs) are crucial for normal development and tissue function, and mutations in ECM genes result in a wide range of serious inherited connective tissue disorders. Mutations cause ECM dysfunction by combinations of two mechanisms. First, secretion of the mutated ECM components can be reduced by mutations affecting synthesis or by structural mutations causing cellular retention and/or degradation. Second, secretion of mutant protein can disturb crucial ECM interactions, structure and stability. Moreover, recent experiments suggest that endoplasmic reticulum (ER) stress, caused by mutant misfolded ECM proteins, contributes to the molecular pathology. Targeting ER stress might offer a new therapeutic strategy.
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              The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks.

              Mutations in SMARCAL1 (HARP) cause Schimke immunoosseous dysplasia (SIOD). The mechanistic basis for this disease is unknown. Using functional genomic screens, we identified SMARCAL1 as a genome maintenance protein. Silencing and overexpression of SMARCAL1 leads to activation of the DNA damage response during S phase in the absence of any genotoxic agent. SMARCAL1 contains a Replication protein A (RPA)-binding motif similar to that found in the replication stress response protein TIPIN (Timeless-Interacting Protein), which is both necessary and sufficient to target SMARCAL1 to stalled replication forks. RPA binding is critical for the cellular function of SMARCAL1; however, it is not necessary for the annealing helicase activity of SMARCAL1 in vitro. An SIOD-associated SMARCAL1 mutant fails to prevent replication-associated DNA damage from accumulating in cells in which endogenous SMARCAL1 is silenced. Ataxia-telangiectasia mutated (ATM), ATM and Rad3-related (ATR), and DNA-dependent protein kinase (DNA-PK) phosphorylate SMARCAL1 in response to replication stress. Loss of SMARCAL1 activity causes increased RPA loading onto chromatin and persistent RPA phosphorylation after a transient exposure to replication stress. Furthermore, SMARCAL1-deficient cells are hypersensitive to replication stress agents. Thus, SMARCAL1 is a replication stress response protein, and the pleiotropic phenotypes of SIOD are at least partly due to defects in genome maintenance during DNA replication.
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                Author and article information

                Journal
                Orphanet J Rare Dis
                Orphanet J Rare Dis
                Orphanet Journal of Rare Diseases
                BioMed Central
                1750-1172
                2012
                22 September 2012
                : 7
                : 70
                Affiliations
                [1 ]Provincial Medical Genetics Program, Department of Medical Genetics, Children's and Women's Health Centre of BC, 4500 Oak Street, Room C234, Vancouver, BC, V6H 3N1, Canada
                [2 ]Rare Disease Foundation, Vancouver, British Columbia, Canada
                [3 ]Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
                [4 ]Department of Pathology, Oregon Health and Science University, Portland, Oregon, United States of America
                [5 ]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
                [6 ]Department of Pathology, University of Washington, Seattle, Washington, United States of America
                [7 ]Warren Clinic, Tulsa, Oklahoma, United States of America
                [8 ]Department of Anatomic Pathology, University of British Columbia and Children’s and Women’s Health Centre of British Columbia, Vancouver, British Columbia, Canada
                [9 ]Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
                [10 ]Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
                [11 ]Néphrologie Pédiatrique, Hôpital d’Enfants, Centre Hospitalier Universitaire de Nancy, Vandoeuvre lés Nancy Cedex, France
                [12 ]Department of Endocrinology & Metabolism, Kanagawa Children’s Medical Center, Yokohama, Japan
                [13 ]Department of Pediatric Nephrology, Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
                [14 ]Institute of Mother and Child Healthcare of Serbia, Belgrade, Serbia
                [15 ]Department of Pediatric Nephrology, VU University Medical Center, Amsterdam, The Netherlands
                [16 ]Département de Génétique, Centre Hospitalier Universitaire d’Angers, Angers, France
                [17 ]Medizinische Hochschule Hannover, Kinderklinik, Hannover, Germany
                [18 ]Division of Genetics, Birth Defects and Metabolism, Children's Memorial Hospital, Chicago, Illinois, United States of America
                [19 ]Centre de Référence des Maladies Rènales Rares, Hospices Civils de Lyon and Université de Lyon, Bron Cedex, France
                [20 ]Serviço de Genética, Hospital Santa Maria, Centro Hospitalar Lisoboa Norte, Lisbon, Portugal
                [21 ]Département de Pédiatrie, Hôpital Robert Debré, Paris, France
                [22 ]Department of Internal Medicine, Division of Endocrinology and Metabolism, Cerrahi Hospital, Denizli, Turkey
                [23 ]Pediatric Immunology & Hematology Unit, Necker Hospital, Paris, France
                [24 ]Department of General Pediatrics, Pediatric Nephrology, University Children’s Hospital Münster, Münster, Germany
                [25 ]Department of Medical Genetics, “Aghia Sophia” Children’s Hospital, Athens University Medical School, Athens, Greece
                [26 ]Unidad de Genética Médica, Servicio de Pediatría, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
                [27 ]Oregon Institute on Disability & Development, Child Development and Rehabilitation Center, Oregon Health & Science University, Portland, Oregon, United States of America
                [28 ]Medical Genetics, Mayo Clinic, Rochester, Minnesota, United States of America
                [29 ]Department of Genetics, Kaiser Permanente, San Francisco, California, United States of America
                [30 ]Mercy Pediatrics and Adolescent Clinic, Clear Lake, Iowa, United States of America
                [31 ]Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium
                [32 ]Department of Pediatrics, Immunology Program and Institute for Immunity, Transplantation, and Infection, Stanford University, Stanford, California, United States of America
                [33 ]Divison of Nephrology, Bambino Gesù Children’s Hospital and Research Institute, Rome, Italy
                [34 ]Department of Medical Genetics, Alberta Children’s Hospital, Calgary, Alberta, Canada
                [35 ]Department of Nephrology, Birmingham Children’s Hospital, Birmingham, United Kingdom
                [36 ]Service de Pédiatrie, Centre Hospitalier Régional Universitaire Hôpital Saint-Jacques, Besançon Cedex, France
                [37 ]Consulta de Genética, Hospital Pediátrico de Coimbra, Coimbra, Portugal
                [38 ]Department of Medical Genetics, Pamukkale University Hospital, Denizli, Turkey
                [39 ]Division of Nephrology, Department of Pediatrics, Kosair Children’s Hospital, School of Medicine, University of Louisville, Louisville, Kentucky, United States of America
                [40 ]Universitätsklinikum Essen, Kinderklinik, Essen, Germany
                [41 ]Cape Breton Regional Hospital, Sydney, Nova Scotia, Canada
                [42 ]Institut für Humangenetik, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
                [43 ]Department of Neuropediatrics, Children’s Hospital, Ruhr-University Bochum, Bochum, Germany
                Article
                1750-1172-7-70
                10.1186/1750-1172-7-70
                3568709
                22998683
                b4edbf7b-4a38-44ad-8241-ca6170ba5c1b
                Copyright ©2012 Morimoto et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 March 2012
                : 14 September 2012
                Categories
                Research

                Infectious disease & Microbiology
                schimke immuno-osseous dysplasia,vascular disease,elastin,smarcal1,pulmonary emphysema

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