Genotype–phenotype analysis in Apert syndrome suggests opposite effects of the two recurrent mutations on syndactyly and outcome of craniofacial surgery

Abstract

Apert syndrome is an autosomal dominant condition characterized by craniosynostosis and severe syndactyly, caused by two recurrent mutations in the fibroblast growth factor receptor 2 gene (FGFR2). The genotype-phenotype correlations of 21 patients with Apert syndrome were analysed as to the craniofacial appearance following surgery and the degree of syndactlyly. The craniofacial appearance following craniofacial surgery was better in patients with the P253R mutation, whereas these patients showed a more pronounced severity of the syndactyly.

Abnormalities in cartilage and bone development in the Apert syndrome FGFR2+/S252W mouse

“…Although, severe syndactyly is a key feature of Apert syndrome in humans, none of the mutant mice from either laboratory exhibited syndactyly by gross inspection and histopathology. The absence of this feature is consistent with the possibility that this mutation causes less severe digital abnormalities in humans when compared with the Apert FGFR2 P253R mutation (Slaney et al, 1996;von Gernet et al, 2000). Others speculate that there is no human phenotypic difference for these two mutations (Park et al, 1995).…”

“…Ninety-nine percent of reported cases have one of two missense mutations in adjacent amino acids, Ser252Trp and Pro253Arg, of fibroblast growth factor receptor 2 (FGFR2) (Park et al, 1995;Wilkie et al, 1995). The first mutation, S252W, is more common, occurring in 67% of patients, and has been proposed to be associated with more severe craniofacial anomalies, whereas the second mutation, P253R, may be associated with more severe syndactyly (Slaney et al, 1996;von Gernet et al, 2000). Both mutations affect the highly conserved linker region between the immunoglobulin-like II and III domains and result in increased affinity and altered specificity of fibroblast growth factor (FGF) ligand binding (Ibrahimi et al, 2001;Yu et al, 2000).…”

Inhibition or Activation of Apert Syndrome FGFR2 (S252W) Signaling by Specific Glycosaminoglycans

“…BaF3 cells make low levels of GAGs (ϳ74 ng/10 6 cells, ϳ20% HS (ϳ14 ng/10 6 cells), and ϳ80% CS (ϳ60 ng/10 6 cells)). 4 In contrast, most mammalian cells make 50 -500 ng/10 6 HS (33). Fetal bovine serum used in the cell culture also contains an appreciable amount of HS and CS.…”

“…The vast majority of Apert syndrome patients have one of two missense mutations in adjacent amino acids, S252W or P253R, of fibroblast growth factor receptor 2 (FGFR2) 2 (1, 2), occasionally patients have an Alu-element insertion in the FGFR2 gene (3). The S252W mutation, found in two-thirds of Apert patients, has been associated with the most severe craniofacial anomalies and dermatological disorders (4,5). The P253R mutation is associated with more severe fusion of the bones in fingers and toes (4,5).…”

“…The S252W mutation, found in two-thirds of Apert patients, has been associated with the most severe craniofacial anomalies and dermatological disorders (4,5). The P253R mutation is associated with more severe fusion of the bones in fingers and toes (4,5). Both crystallographic and biochemical studies of FGFR2 (S252W) and (P253R) mutants with various FGFs indicate that the mutations, in the highly conserved linker region between the immunoglobulin-like domains II and III, resulted in increased affinity and altered specificity of FGF ligand binding (6 -9).…”