Cloning and Sequencing of the Rabbit FGFR2 cDN A

Normal development of the mammalian skull requires differentiation and coordination of all the outgrowing bones, particularly at sites of articulation knows as sutures. Such growth is necessary to accommodate an enlarging brain., Approximately 1 in 2500 human infants is born with craniosynostosis, the premature fusion of one or more calvarial sutures. This condition disrupts allometric growth and results in classic craniofacial features, including abnormal head shape, protruding eyes and midface underdevelopment (Hunter and Rudd, 1976; 1977; Lajeunie et al., 1995; 1996). Approximately 100 syndromes which include craniosynostosis are known and these syndromes are usually monogenic with an autosomal dominant mode of transmission. Recently, a number of mutations have been identified in three of the four members of the fibroblast growth factor receptor (FGFR) family as a cause of simple craniosynostosis and syndromes which include craniosynostosis as part of the phenotype, including Pfeiffer, Crouzon and Jackson-Weiss syndromes (Webster and Donoghue, 1997). The FGFRs are high-affinity receptors for the fibroblast growth factors, a family of at least 13 structurally related proteins (Smallwood et al., 1996) involved in a wide range of biological processes, including cell growth, differentiation, migration, wound healing and angiogenesis, depending on the target cell type and developmental stage (Basilico and Moscatelli, 1992; Fernig and Gallagher, 1994). The four FGFRs that have been described thus far exhibit a similar structure, consisting of an extracellular region made of three immunoglobulin-like (Ig-like) domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain (Jaye et al., 1992; Partanen et al., 1993).