Craniosynostosis is the pathologic fusion of the calvaria. Over the past ten years significant advances have been made in our understanding of multiple malformation syndromes that involve craniosynostosis. It has been shown that mutations in the fibroblast growth factor receptors (FGFR1-3), TWIST1, MSX2, and the EFNB1 each cause craniosynostosis syndrome in humans. This extensive body of work, carried out in several international laboratories, has significantly impacted how we diagnose and counsel families with syndromic craniosynostosis. Despite the rapid growth of knowledge regarding syndromic forms, the causes of isolated synostosis remain elusive. Though vastly more common than syndromic forms, relatively little research has focused on the molecular pathogenesis of isolated craniosynostosis. The frequency of this group of calvarial malformations, the need for complex surgical management and its associated morbidity make isolated craniosynostosis a candidate for intense scientific investigation. We propose the use of three approaches to identify and characterize candidate genetic causes of isolated craniosynostosis: high throughput genomic sequencing, large-scale microarray expression analysis, and developmental gene expression. We have used knowledge gained from the investigation of normal calvarial development and syndromic forms of craniosynostosis to develop two interrelated hypotheses: (A) Rare sequence variants in two classes of genes result in isolated craniosynostosis: those that regulate suture development and those that, when mutated, cause syndromic craniosynostosis;and (B) Genetic pathways involved in cranial suture development and those impacted in the syndromic craniosynostoses are similarly affected in isolated, non-syndromic craniosynostosis. In this proposal, we describe a series of experiments designed to discover potential molecular causes of isolated craniosynostosis through the identification of rare genetic variants, altered calvarial osteoblast gene expression, and the temporal and spatial expression of candidate genes. The expertise of our research team and the availability of complementary high throughput approaches has allowed for the development of a comprehensive investigation of the genetic and developmental pathogenesis of isolated craniosynostosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE018227-05
Application #
8044794
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Harris, Emily L
Project Start
2008-03-25
Project End
2013-02-28
Budget Start
2011-03-01
Budget End
2013-02-28
Support Year
5
Fiscal Year
2011
Total Cost
$166,867
Indirect Cost
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
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Al-Rekabi, Zeinab; Wheeler, Marsha M; Leonard, Andrea et al. (2016) Activation of the IGF1 pathway mediates changes in cellular contractility and motility in single-suture craniosynostosis. J Cell Sci 129:483-91
Homayounfar, Negar; Park, Sarah S; Afsharinejad, Zahra et al. (2015) Transcriptional analysis of human cranial compartments with different embryonic origins. Arch Oral Biol 60:1450-60
Speltz, Matthew L; Collett, Brent R; Wallace, Erin R et al. (2015) Intellectual and academic functioning of school-age children with single-suture craniosynostosis. Pediatrics 135:e615-23
Carmichael, S L; Ma, C; Rasmussen, S A et al. (2015) Craniosynostosis and risk factors related to thyroid dysfunction. Am J Med Genet A 167A:701-7
Park, Sarah S; Beyer, Richard P; Smyth, Matthew D et al. (2015) Osteoblast differentiation profiles define sex specific gene expression patterns in craniosynostosis. Bone 76:169-76
Kim, Sun-Don; Yagnik, Garima; Cunningham, Michael L et al. (2014) MAPK/ERK Signaling Pathway Analysis in Primary Osteoblasts From Patients With Nonsyndromic Sagittal Craniosynostosis. Cleft Palate Craniofac J 51:115-9
Stamper, Brendan D; Park, Sarah S; Beyer, Richard P et al. (2012) Unique sex-based approach identifies transcriptomic biomarkers associated with non-syndromic craniosynostosis. Gene Regul Syst Bio 6:81-92
Justice, Cristina M; Yagnik, Garima; Kim, Yoonhee et al. (2012) A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat Genet 44:1360-4
Yagnik, Garima; Ghuman, Apar; Kim, Sundon et al. (2012) ALX4 gain-of-function mutations in nonsyndromic craniosynostosis. Hum Mutat 33:1626-9

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