elastin and Primary-Immunodeficiency-Diseases

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.. 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.. 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.. 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.

Topics: Adolescent; Adult; Aorta; Arteriosclerosis; Case-Control Studies; Cells, Cultured; Child; Child, Preschool; DNA Methylation; Down-Regulation; Elastin; Female; Gestational Age; Humans; Immunologic Deficiency Syndromes; Male; MicroRNAs; Middle Aged; Nephrotic Syndrome; Osteochondrodysplasias; Primary Immunodeficiency Diseases; Promoter Regions, Genetic; Pulmonary Embolism; RNA Precursors; RNA Processing, Post-Transcriptional; RNA, Messenger; Transcription Factors; Transcription, Genetic