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Calvarial osteoblast gene expression in patients with craniosynostosis leads to novel polygenic mouse model.
PLoS One 2019; 14(8):e0221402Plos

Abstract

Craniosynostosis is the premature fusion of the sutures of the calvaria and is principally designated as being either syndromic (demonstrating characteristic extracranial malformations) or non-syndromic. While many forms of syndromic craniosynostosis are known to be caused by specific mutations, the genetic etiology of non-syndromic, single-suture craniosynostosis (SSC) is poorly understood. Based on the low recurrence rate (4-7%) and the fact that recurrent mutations have not been identified for most cases of SSC, we propose that some cases of isolated, single suture craniosynostosis may be polygenic. Previous work in our lab identified a disproportionately high number of rare and novel gain-of-function IGF1R variants in patients with SSC as compared to controls. Building upon this result, we used expression array data from calvarial osteoblasts isolated from infants with and without SSC to ascertain correlations between high IGF1 expression and expression of other osteogenic genes of interest. We identified a positive correlation between increased expression of IGF1 and RUNX2, a gene known to cause SSC with increased gene dosage. Subsequent phosphorylation assays revealed that osteoblast cell lines from cases with high IGF1 expression demonstrated inhibition of GSK3β, a serine/threonine kinase known to inhibit RUNX2, thus activating osteogenesis through the IRS1-mediated Akt pathway. With these findings, we have utilized established mouse strains to examine a novel model of polygenic inheritance (a phenotype influenced by more than one gene) of SSC. Compound heterozygous mice with selective disinhibition of RUNX2 and either overexpression of IGF1 or loss of function of GSK3β demonstrated an increase in the frequency and severity of synostosis as compared to mice with the RUNX2 disinhibition alone. These polygenic mouse models reinforce, in-vivo, that the combination of activation of the IGF1 pathway and disinhibition of the RUNX2 pathway leads to an increased risk of developing craniosynostosis and serves as a model of human SSC.

Authors+Show Affiliations

Seattle Children's Research Institute, Center for Developmental Biology and Regenerative Medicine, Seattle, Washington, United States of America.Seattle Children's Research Institute, Center for Developmental Biology and Regenerative Medicine, Seattle, Washington, United States of America.Seattle Children's Research Institute, Center for Developmental Biology and Regenerative Medicine, Seattle, Washington, United States of America. Seattle Children's Hospital Craniofacial Center, Seattle, Washington, United States of America. University of Washington, Department of Pediatrics, Seattle, Washington, United States of America.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31442251

Citation

Gustafson, Jonas A., et al. "Calvarial Osteoblast Gene Expression in Patients With Craniosynostosis Leads to Novel Polygenic Mouse Model." PloS One, vol. 14, no. 8, 2019, pp. e0221402.
Gustafson JA, Park SS, Cunningham ML. Calvarial osteoblast gene expression in patients with craniosynostosis leads to novel polygenic mouse model. PLoS ONE. 2019;14(8):e0221402.
Gustafson, J. A., Park, S. S., & Cunningham, M. L. (2019). Calvarial osteoblast gene expression in patients with craniosynostosis leads to novel polygenic mouse model. PloS One, 14(8), pp. e0221402. doi:10.1371/journal.pone.0221402.
Gustafson JA, Park SS, Cunningham ML. Calvarial Osteoblast Gene Expression in Patients With Craniosynostosis Leads to Novel Polygenic Mouse Model. PLoS ONE. 2019;14(8):e0221402. PubMed PMID: 31442251.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Calvarial osteoblast gene expression in patients with craniosynostosis leads to novel polygenic mouse model. AU - Gustafson,Jonas A, AU - Park,Sarah S, AU - Cunningham,Michael L, Y1 - 2019/08/23/ PY - 2019/01/29/received PY - 2019/08/06/accepted PY - 2019/8/24/entrez PY - 2019/8/24/pubmed PY - 2019/8/24/medline SP - e0221402 EP - e0221402 JF - PloS one JO - PLoS ONE VL - 14 IS - 8 N2 - Craniosynostosis is the premature fusion of the sutures of the calvaria and is principally designated as being either syndromic (demonstrating characteristic extracranial malformations) or non-syndromic. While many forms of syndromic craniosynostosis are known to be caused by specific mutations, the genetic etiology of non-syndromic, single-suture craniosynostosis (SSC) is poorly understood. Based on the low recurrence rate (4-7%) and the fact that recurrent mutations have not been identified for most cases of SSC, we propose that some cases of isolated, single suture craniosynostosis may be polygenic. Previous work in our lab identified a disproportionately high number of rare and novel gain-of-function IGF1R variants in patients with SSC as compared to controls. Building upon this result, we used expression array data from calvarial osteoblasts isolated from infants with and without SSC to ascertain correlations between high IGF1 expression and expression of other osteogenic genes of interest. We identified a positive correlation between increased expression of IGF1 and RUNX2, a gene known to cause SSC with increased gene dosage. Subsequent phosphorylation assays revealed that osteoblast cell lines from cases with high IGF1 expression demonstrated inhibition of GSK3β, a serine/threonine kinase known to inhibit RUNX2, thus activating osteogenesis through the IRS1-mediated Akt pathway. With these findings, we have utilized established mouse strains to examine a novel model of polygenic inheritance (a phenotype influenced by more than one gene) of SSC. Compound heterozygous mice with selective disinhibition of RUNX2 and either overexpression of IGF1 or loss of function of GSK3β demonstrated an increase in the frequency and severity of synostosis as compared to mice with the RUNX2 disinhibition alone. These polygenic mouse models reinforce, in-vivo, that the combination of activation of the IGF1 pathway and disinhibition of the RUNX2 pathway leads to an increased risk of developing craniosynostosis and serves as a model of human SSC. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/31442251/Calvarial_osteoblast_gene_expression_in_patients_with_craniosynostosis_leads_to_novel_polygenic_mouse_model L2 - http://dx.plos.org/10.1371/journal.pone.0221402 DB - PRIME DP - Unbound Medicine ER -