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. 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 (Cunningham ML, Horst JA, Rieder MJ, Hing AV, Stanaway IB, Park SS, Samudrala R, Speltz ML. Am J Med Genet A 155A: 91-97, 2011). Elevated IRS1 (pan-tyr) and GSK3ß (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), GSK3ß (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.
Subject(s)
Craniosynostoses/genetics , Insulin Receptor Substrate Proteins/genetics , Transcriptional Activation , Transcriptome/genetics , Cell Line , Cells, Cultured , Child , Child, Preschool , Cluster Analysis , Craniosynostoses/classification , Craniosynostoses/pathology , Glycogen Synthase Kinase 3/genetics , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Infant , Insulin Receptor Substrate Proteins/metabolism , JNK Mitogen-Activated Protein Kinases/genetics , JNK Mitogen-Activated Protein Kinases/metabolism , Mutation , Oligonucleotide Array Sequence Analysis , Osteoblasts/cytology , Osteoblasts/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/metabolism , Ribosomal Protein S6/genetics , Ribosomal Protein S6/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Signal Transduction/genetics , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
PIP: This article critically examines 4 conceptual frameworks for Third World population policies: the family planning approach, beyond family planning measures, the development hypothesis and transition theory, and the distributive hypothesis and fertility. Although family planning is a basic human right and can lead to lower levels of population and improved maternal-child health, this approach alone does not always have a meaningful demographic impact. If high fertility is economically rational from the family viewpoint, the demand for family planning services will remain marginal. Other policies seek to go beyond the family planning approach and to directly influence the demand for reproductive control through provision of old age support, monetary incentives for reduced fertility or stringent and coercive measures. However, such policies can have adverse distributional effects and directly penalize the children of large families. The demographic transition theory lacks a measurable and specifiable causation mechanism, giving it little predictive value. It may be that economic growth increases fertility in the short run and reduces fertility only over the long run through indirect effects. The key issue is how the rate of growth is distributed across the population. The development and demographic transition hypothesis focuses mainly on aggregate economic and social measures rather than on their underlying distributions. The distributive hypothesis implies policies that promote a greater level of investment in human capital, with a wide distributional emphasis. Diffused investment in human capital is believed to indirectly influence the desire to control fertility. It is concluded that all 4 conceptual frameworks for analyzing fertility-related policies for the Third World are inadequate or seriously flawed. They are not pragmatic, do not identify or assign weights to the crucial causal variables, fail to specify thresholds or critical minimum levels, discount cultural settings, and ignore the manipulability of key variables.^ieng