Research
Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?
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
Orphanet Journal of Rare Diseases 2012, 7:70 doi:10.1186/1750-1172-7-70
Published: 22 September 2012Abstract
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.
