Marie Morimoto1,2, Karen J Wang1,2, Zhongxin Yu3, Andrew K Gormley4, David Parham5, Radovan Bogdanovic6,7, Thomas Lücke8, Christy Mayfield9, Rosanna Weksberg10, Glenda Hendson11,12, Cornelius F Boerkoel1,2. 1. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. 2. Child and Family Research Institute, Vancouver, British Columbia, Canada. 3. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. 4. Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. 5. Department of Pathology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California. 6. Department of Nephrology, Institute of Mother and Child Healthcare of Serbia, Belgrade, Serbia. 7. Department of Pediatrics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. 8. Department of Neuropediatrics, Children's Hospital, Ruhr-University Bochum, Bochum, Germany. 9. Warren Clinic, Tulsa, Oklahoma. 10. Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 11. Department of Anatomic Pathology, University of British Columbia, Vancouver, British Columbia, Canada. 12. Department of Anatomic Pathology, Children's and Women's Health Centre of British Columbia, Vancouver, British Columbia, Canada.
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. CONCLUSION: 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.
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. CONCLUSION: 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: Alison K Ward; Paul Mellor; Shari E Smith; Stephanie Kendall; Natasha A Just; Frederick S Vizeacoumar; Sabuj Sarker; Zoe Phillips; Riaz Alvi; Anurag Saxena; Franco J Vizeacoumar; Svein A Carlsen; Deborah H Anderson Journal: Breast Cancer Res Date: 2016-01-25 Impact factor: 6.466