%0 Journal Article
%T Molecular Analysis of Twist1 and FGF Receptors in a Rabbit Model of Craniosynostosis: Likely Exclusion as the Loci of Origin
%A Phillip H. Gallo
%A James J. Cray Jr.
%A Emily L. Durham
%A Mark P. Mooney
%A Gregory M. Cooper
%A Sandeep Kathju
%J International Journal of Genomics
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/305971
%X Craniosynostosis is the premature fusion of the cranial vault sutures. We have previously described a colony of rabbits with a heritable pattern of nonsyndromic, coronal suture synostosis; however, the underlying genetic defect remains unknown. We now report a molecular analysis to determine if four genes implicated in human craniosynostosis, TWIST1 and fibroblast growth factor receptors 1¨C3 (FGFR1¨C3), could be the loci of the causative mutation in this unique rabbit model. Single nucleotide polymorphisms (SNPs) were identified within the Twist1, FGFR1, and FGFR2 genes, and the allelic patterns of these silent mutations were examined in 22 craniosynostotic rabbits. SNP analysis of the Twist1, FGFR1, and FGFR2 genes indicated that none were the locus of origin of the craniosynostotic phenotype. In addition, no structural mutations were identified by direct sequence analysis of Twist1 and FGFR3 cDNAs. These data indicate that the causative locus for heritable craniosynostosis in this rabbit model is not within the Twist1, FGFR1, and FGFR2 genes. Although a locus in intronic or flanking sequences of FGFR3 remains possible, no direct structural mutation was identified for FGFR3. 1. Introduction Craniosynostosis (CS) is the premature fusion of one or more of the fibrous joints of the calvaria (cranial sutures). If this synostosis happens early enough in human development, it can lead to alterations in skull shape, reduced cranial growth, increased intracranial pressure, impaired blood flow, impaired vision and hearing, as well as mental retardation [1¨C7]. In most cases, surgical intervention is necessary to improve the patient¡¯s prognosis [8¨C11]. There are extensive signaling networks present within the cranial sutures that allow for the coordinated growth of the skull [12]. One such network involves the fibroblast growth factor receptors (FGFRs). FGFRs belong to a family of tyrosine kinase receptors that exhibit a common organization, including two or three extracellular immunoglobulin (Ig) like binding domains, a transmembrane domain, and two intracellular tyrosine kinase subdomains [13]. The binding of FGF to FGFR in association with heparin sulphate proteoglycan (HSPG) induces receptor dimerization at the cell surface. This dimerization in turn leads to autophosphorylation that triggers phosphorylation of downstream signaling proteins [13]. In calvarial sutures, FGFs are secreted by osteoblasts at the differentiated edge of the bones; they activate receptors involved in both osteoprogenitor cell proliferation and function in the conversion of these cells
%U http://www.hindawi.com/journals/ijg/2013/305971/