Transcriptome correlation analysis identifies two unique craniosynostosis subtypes associated with IRS1 activation

ArticleinPhysiological Genomics 44(23) · October 2012with4 Reads
DOI: 10.1152/physiolgenomics.00085.2012 · Source: PubMed
Abstract
The discovery of causal mechanisms associated with nonsyndromic craniosynostosis has proven to be a difficult task due to the complex nature of the disease. In this study, differential transcriptome correlation analysis was used to identify two molecularly distinct subtypes of nonsyndromic craniosynostosis, termed subtype A and subtype B. In addition to unique correlation structure, subtype A was also associated with high IGF pathway expression, whereas subtype B was associated with high integrin expression. In order to identify a pathologic link between altered gene correlation/expression and the disease state, phosphorylation assays were performed on primary osteoblast cell lines derived from cases within subtype A or subtype B, as well as on primary osteoblast cell lines with novel IGF1R variants previously reported by our lab (5). Elevated IRS1 (pan-tyr) and GSK3β (ser-9) phosphorylation were observed in two novel IGF1R variants with receptor L domain mutations. In subtype A, a hypomineralization phenotype coupled with decreased phosphorylation of IRS1 (ser-312), p38 (thr-180/tyr-182), and p70S6K (thr-412) was observed. In subtype B, decreased phosphorylation of IRS1 (ser-312) as well as increased phosphorylation of Akt (ser-473), GSK3β (ser-9), IGF1R (tyr-1135/tyr-1136), JNK (thr-183/tyr-187), p70S6K (thr-412) and pRPS6 (ser-235/ser-236) was observed, thus implicating the activation of IRS1-mediated Akt signaling in potentiating craniosynostosis in this subtype. Taken together, these results suggest that despite the stimulation of different pathways, activating phosphorylation patterns for IRS1 were consistent in cell lines from both subtypes and the IGF1R variants, thus implicating a key role for IRS1 in the pathogenesis of nonsyndromic craniosynostosis.
    • "Examination of the association of CS with variants in genes that are most proximal to thyroid hormone synthesis and biologic activity, such as those mentioned above, would certainly be informative. Bioinformatic approaches that examine gene expression correlation structures may also be useful [53]. As a preliminary demonstration of this approach, we examined publicly available data that reflect changes in gene expression subsequent to T 4 exposure (Gene Expression Omnibus " GEO " GSE32444, 47517, and 15458). "
    [Show abstract] [Hide abstract] ABSTRACT: Craniosynostosis, the premature fusion of one or more cranial sutures, leads to abnormal craniofacial form and function. Its causes remain largely unknown. One of the strongest clues regarding non-syndromic craniosynostosis etiology is its association with thyroid-related disorders, which is based on a mix of epidemiologic and experimental findings. This paper reviews evidence for the contribution of thyroid-related mechanisms to craniosynostosis and makes recommendations for how to improve this knowledge.
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    • "Using lymphoblasts cell lines derived from HD patients and control siblings, we evaluated the insulin/IGF-1 signaling pathways. Our results demonstrate that IR,IGF-1R phosphorylation at Tyr1158, 1162, and 1163, previously described to reflect their activation [24, 44], was significantly decreased in HD patient's lymphoblasts (Fig. 1ai), whereas no significant changes were observed in IR,IGF-1R protein levels (Fig. 1a, ii ). Exposure to IGF-1 (0.1 nM) enhanced IR,IGF-1R activation in HD cells by about 2-fold, whereas no changes in IR,IGF-1R activation were observed in the presence of insulin (0.1 nM). "
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