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. 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.S chimke immuno-osseous dysplasia (SIOD, OMIM 242900) is a rare autosomal recessive multisystemic disorder caused by mutations in the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) gene (1). SMARCAL1 functions as a DNA-dependent annealing helicase (2) that recognizes single-stranded to double-stranded DNA transitions and binds to transcriptionally active chromatin (3). SMARCAL1 is involved in the DNA stress response (4,5), the reactivation of stalled replication forks (6)(7)(8), and the modulation of gene expression (3). Key manifestations of the disease include growth failure due to spondyloepiphyseal dysplasia, renal failure due to focal segmental glomerulosclerosis, T-cell immunodeficiency, facial dysmorphism, and hyperpigmented macules (9). Approximately 50% of SIOD patients also develop vascular disease (10), and the vascular complications are refractory to treatment and a common cause of death (11).The vascular disease in SIOD manifests as migraine-like headaches, transient ischemic attacks, and cerebrovascular accidents (11). The arterial histopathology shows intimal and medial hyperplasia, smooth muscle cell hyperplasia, and fragmented and disorganized elastin fibers (10,12). Molecular studies suggest reduced elastogenesis (10); however, the mechanism underlying this remains unknown.Elastin, which is critical for the development and maintenance of the arteries (13,14), confers the elastic recoil properties required for the proper function of the arteries as well as other load-bearing...

Inducible SMARCAL1 knockdown in iPSC reveals a link between replication stress and altered expression of master differentiation genes

“…Most importantly, loss of SMARCAL1 affects expression of a subset of germ layer-specific master genes, which can be rescued through inhibition of DDR signalling. The pathogenetic mechanisms responsible for SIOD are still elusive; however, SMARCAL1 deficiency has been reported to pathologically modulate gene expression (Baradaran-Heravi et al, 2012; Morimoto et al, 2015, 2016a,b; Sanyal et al, 2015). An intriguing possibility is that loss of SMARCAL1 function indirectly influences gene expression through increased levels of replication stress, as has been suggested for loss of WRN or FANCJ helicase (BRIP1) (Khurana and Oberdoerffer, 2015; Papadopoulou et al, 2015; Schiavone et al, 2014).…”

SMARCAL1, the annealing helicase and the transcriptional co‐regulator

“…It has long been hypothesized that SMARCAL1 might be transcriptionally regulating a subset of genes, and failure of this process results in pathophysiological features associated with various diseases. 8,[55][56][57] Baradaran-Heravi postulated that SMARCAL1 with its ability to recognize specific DNA structure would be able to regulate the expression of genes such as c-kit because of the presence of specific structures in their promoters. 58 The first evidence that the hypothesis might be true came from studies where SMARCAL1 was shown to negatively regulate the expression of c-MYC 7 (Figure 3).…”

Moyamoya Syndrome in Schimke Immune-Osseous Dysplasia: A Rare Association

“…Schimke immuno-osseous dysplasia (SIOD) is an uncommon AR disorder due to mutations in the SMARCAL1 gene, which encodes for chromatin-remodeling enzyme necessary for stabilizing stalled replication forks, restricting DNA damage due to its replication [ 1 ]. The vascular changes in this disorder are due to disorganized elastogenesis with reduced elastin expression within the vessel, resulting in the defective internal elastic lamina and hyperplasia of intima or media [ 3 ]. This disorder manifests as spondylo-epiphyseal dysplasia (SED), immunodeficiency, growth retardation, and nephropathy.…”