Identification and functional analysis of mutations associated with craniosynostosis

Author(s)

Rodrigo Atique Ferraz de Toledo

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB)
• Defense date: 2016-09-23

Examining board members

Maria Rita dos Santos e Passos Bueno; Ana Carolina Acevedo; Débora Romeo Bertola; Roseli Maria Zechi Ceide; Regina Celia Mingroni Netto

• Advisor: Maria Rita dos Santos e Passos Bueno

Abstract

Craniosynostosis are craniofacial malformations defined by early closure of the cranial sutures. They are congenital diseases caused by mutations in several genes due to the diversity of pathways involved in the development and maintenance of the cranial sutures. Even though 53 genes have already been linked to various forms of craniosynostosis, the knowledge about the genetics and pathophysiology is incomplete. In this work we aimed to identify new mutations associated with craniosynostosis as well as to further the knowledge of how those mutations act in human cells. To identify new variants associated with craniosynostosis we used large scale sequencing techniques known as next generation sequencing (NGS). We were able to identify the causal mutation in one patient from a consanguineous marriage with Raine syndrome (p.P496L in FAM20C). We also were able to elect candidate mutations in other eleven cases of atypical craniosynostosis. Lastly, we studied the effects of different FGFs over the behavior of human cells harboring the most common Apert syndrome mutation, p.S252W in FGFR2. We discovered that FGFs 10 and 19 have different effects over the transcriptional profile and proliferation rate of mutant cells. We also found that FGF19 have opposite effects in mesenchymal stem cells and fibroblastoid cells osteogenic differentiation. The results shown here will be of great service to better understand the biology of cranial suture and the pathophysiology of craniosynostosis (AU)

• FAPESP's process: 12/25346-4 - Identification and functional analysis of new mutations associated to craniosynostosis
• Grantee: Rodrigo Atique Ferraz de Toledo
• Support Opportunities: Scholarships in Brazil - Doctorate