Molecular analysis of syndromic craniosynostosis: Crouzon, Pfeiffer and Saethre-Chotzen

Author(s)

Nélio Alessandro de Jesus Oliveira

• Document type: Master's Dissertation
• Press: São Paulo. , gráficos, tabelas.
• Institution: Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB)
• Defense date: 2006-09-11

Examining board members

Maria Rita dos Santos e Passos Bueno; Luis Garcia Alonso; Celia Priszkulnik Koiffmann

• Advisor: Maria Rita dos Santos e Passos Bueno
• Field of knowledge: Biological Sciences - Genetics
• Indexed in: Banco de Dados Bibliográficos da USP-DEDALUS; Biblioteca Digital de Teses e Dissertações - USP
• Location: Universidade de São Paulo. Biblioteca do Instituto de Biociências; IB/M-1258

Abstract

Craniosynostosis, defined as the premature fusion of one or more cranial suture, are a very heterogeneous group of disorders, with an occurrence of about 1: 2000 live births. Except for rare syndromes, such as Apert, most of the cranioysnostotic conditions are characterized by wide clinical variability and genetic heterogeneity. Craniosynostosis can be classified into non syndromic forms - premature suture fusion is the only clinical alteration, and syndromic ones - premature cranial suture fusion associated with other anomalies. Apert, Pfeiffer, Crouzon and Saethre-Chotzen are the most common syndromic forms of craniosynostosis. The mutational mechanism is identified in approximately 58% of patients with Crouzon syndrome: FGFR2 mutations account for most of the cases (more than 80%) while mutations in TWIST1 and FGFR3 causes the remaining of them. Therefore, about 42% of the cases with clinical characteristics of Crouzon syndrome do not harbor mutations in any of these 3 genes and other mutational mechanisms might be responsible for the phenotype. Approximately 45% of Pfeiffer syndrome cases is not caused by mutations in the FGFR1 or FGFR2 genes, thus also suggesting genetic heterogeneity for this phenotype. On the other hand, all cases with Apert syndrome are caused by specific mutations in FGFR2. FGFR2 mutations show a partial genotype-phenotype correlation; however, severe cases, such as Pfeiffer types II and III are still very poorly characterized. Retroviral insertion experiments in mouse lead to the identification of animals with a phenotype that resembles Crouzon syndrome. It was suggested that this phenotype was caused by upregulation of the FGF3 and FGF4 genes as a consequence of the insertion of the retrovirus between these 2 genes . In addition, implantation of beads with FGF4 in the cranium of neonatal mice has increased the fusion of the cranium sutures . Therefore, it is possible that gain of function mutations in the FGF3 e FGF4 genes might lead to Crouzon or syndromic craniosynostosis.Characterization of pathogenic mutations in the TWIST1 gene among patients with Saethre-Chotzen syndrome has contributed for a better understanding of the protein domains of the corresponding protein. These mutations, which are missense or null, cause loss of function of the protein and haploinsufficiency of the TWIST1 gene has been postulated as the mechanism model for Saethre-Chotzen syndrome.Up to now, only pathogenic mutations in coding regions have been associated with the disease and there is very little information about the effect of mutations on the regulatory regions of the TWIST1 gene on the phenotype.Considering the above information, the aims of the present work were: a) verify if mutations in FGF3 and FGF4 can cause craniosynostosis; b) verify if the severe phenotype in a patient Pfeiffer type 3 is due to a specific mutation in FGFR2; c) identify mutations in 7 patients with Saethre-Chotzen syndrome; d) verify if a mutation in the regulatory region of the TWIST1 gene can cause craniosynostosis. (AU)