title: Transcriptional and posttranscriptional mechanisms contribute to the dysregulation of elastogenesis in Schimke immuno-osseous dysplasia.
abstract: BACKGROUND
  Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by mutations in SMARCAL1. A frequent complication is arteriosclerosis associated with reduced elastin expression; however, the mechanism underlying the reduced elastin expression remains unknown.
  
  
  METHODS
  Expression of transcriptional regulators of elastin (ELN) and microRNA (miRNA) regulators of ELN messenger RNA (mRNA), ELN promoter methylation, and ELN mRNA poly(A) tail length were assessed by quantitative RT-PCR, bisulfite Sanger sequencing, and the Poly(A) Tail Length Assay Kit, respectively, in unaffected developing human aortae and in an SIOD aorta.
  
  
  RESULTS
  Comparing unaffected fetal and adult aortae, ELN precursor mRNA (pre-mRNA) levels remained nearly constant, whereas mRNA levels declined by ~10(2)-fold. This corresponded with a reduction in poly(A) tail length but not with changes in the other parameters. In contrast, compared to the unaffected fetal aortae, the SIOD aorta had 18-fold less ELN pre-mRNA and 10(4)-fold less mRNA. This corresponded with increased expression of miRNA regulators and shorter ELN mRNA poly(A) tail lengths but not with altered expression of ELN transcriptional regulators or ELN promoter methylation.
  
  
  CONCLUSIONS
  Posttranscriptional mechanisms account for the reduction in ELN mRNA levels in unaffected aortae, whereas transcriptional and posttranscriptional mechanisms reduce elastin expression in SIOD aorta and predispose to arteriosclerosis.
authors: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.|Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors: Marie
authors: M
authors: Morimoto
authors: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.|Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors: Karen J
authors: KJ
authors: Wang
authors: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors: Zhongxin
authors: Z
authors: Yu
authors: Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors: Andrew K
authors: AK
authors: Gormley
authors: Department of Pathology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors: David
authors: D
authors: Parham
authors: Department of Nephrology, Institute of Mother and Child Healthcare of Serbia, Belgrade, Serbia.|Department of Pediatrics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
authors: Radovan
authors: R
authors: Bogdanovic
authors: Department of Neuropediatrics, Children's Hospital, Ruhr-University Bochum, Bochum, Germany.
authors: Thomas
authors: T
authors: Lücke
authors: Warren Clinic, Tulsa, Oklahoma.
authors: Christy
authors: C
authors: Mayfield
authors: Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors: Rosanna
authors: R
authors: Weksberg
authors: Department of Anatomic Pathology, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Anatomic Pathology, Children's and Women's Health Centre of British Columbia, Vancouver, British Columbia, Canada.
authors: Glenda
authors: G
authors: Hendson
authors: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.|Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors: Cornelius F
authors: CF
authors: Boerkoel
mesh_terms: D000293:Adolescent; D000328:Adult; D001011:Aorta / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D001161:Arteriosclerosis / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D015536:Down-Regulation; D004549:Elastin / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005865:Gestational Age; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009404:Nephrotic Syndrome / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010009:Osteochondrodysplasias / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000081207:Primary Immunodeficiency Diseases; D011401:Promoter Regions, Genetic; D011655:Pulmonary Embolism / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D035683:MicroRNAs; D012322:RNA Precursors; D012333:RNA, Messenger; D014157:Transcription Factors; D004549:Elastin