TY - JOUR
T1 - Reduced elastogenesis
T2 - A clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?
AU - Morimoto, Marie
AU - Yu, Zhongxin
AU - Stenzel, Peter
AU - Clewing, J. Marietta
AU - Najafian, Behzad
AU - Mayfield, Christy
AU - Hendson, Glenda
AU - Weinkauf, Justin G.
AU - Gormley, Andrew K.
AU - Parham, David M.
AU - Ponniah, Umakumaran
AU - André, Jean Luc
AU - Asakura, Yumi
AU - Basiratnia, Mitra
AU - Bogdanović, Radovan
AU - Bokenkamp, Arend
AU - Bonneau, Dominique
AU - Buck, Anna
AU - Charrow, Joel
AU - Cochat, Pierre
AU - Cordeiro, Isabel
AU - Deschenes, Georges
AU - Fenkçi, M. Semin
AU - Frange, Pierre
AU - Fründ, Stefan
AU - Fryssira, Helen
AU - Guillen-Navarro, Encarna
AU - Keller, Kory
AU - Kirmani, Salman
AU - Kobelka, Christine
AU - Lamfers, Petra
AU - Levtchenko, Elena
AU - Lewis, David B.
AU - Massella, Laura
AU - McLeod, D. Ross
AU - Milford, David V.
AU - Nobili, François
AU - Saraiva, Jorge M.
AU - Semerci, C. Nur
AU - Shoemaker, Lawrence
AU - Stajić, Nataša
AU - Stein, Anja
AU - Taha, Doris
AU - Wand, Dorothea
AU - Zonana, Jonathan
AU - Lücke, Thomas
AU - Boerkoel, Cornelius F.
N1 - Funding Information:
We are grateful to all of our patients and family members who have contributed to this study. We thank Theresa Sturby, Barbara A. Antalffy and Pauline Grennan for preparation of tissue. This work was supported in part by grants from the March of Dimes (6-FY02-136 to CF Boerkoel), the Gillson Longenbaugh Foundation (CF Boerkoel), the Dana Foundation (CF Boerkoel) and the New Development Award, Microscopy, and Administrative Cores of the Mental Retardation and Developmental Disabilities Research Center at Baylor College of Medicine (CF Boerkoel), the Burroughs Wellcome Foundation (1003400 to CF Boerkoel), the National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health (R03 DK062174 and R21DK065725 to CF Boerkoel), New Investigator Award from the SickKids Foundation – Canadian Institutes of Health Research: Institute of Human Development, Child and Youth Health (CF Boerkoel), the Michael Smith Foundation for Health Research (CI-SCH-O1899(07–1) to CF Boerkoel), the Association Autour D’Emeric et D’Anthony (CF Boerkoel) and The Little Giants Foundation (CF Boerkoel). CF Boerkoel is a scholar of the Michael Smith Foundation for Health Research and a Clinical Investigator of the Child & Family Research Institute.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Elastin
KW - Pulmonary emphysema
KW - SMARCAL1
KW - Schimke immuno-osseous dysplasia
KW - Vascular disease
UR - http://www.scopus.com/inward/record.url?scp=84866491739&partnerID=8YFLogxK
U2 - 10.1186/1750-1172-7-70
DO - 10.1186/1750-1172-7-70
M3 - Article
C2 - 22998683
AN - SCOPUS:84866491739
VL - 7
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
SN - 1750-1172
IS - 1
M1 - 70
ER -