Molecular Genetics and Pathophysiology

Abstract This chapter discusses the genetic mutations that cause Apert syndrome, how these lead to its characteristic clinical manifestations, and how the two canonical heterozygous mutations (which encode the amino acid substitutions p.Ser252Trp and p.Pro253Arg, located in the extracellular part of the fibroblast growth factor [FGF] receptor 2 [FGFR2] protein) were discovered. The structural basis by which these substitutions differentially enhance binding affinity for specific FGF ligands is reviewed; this ligand-dependent gain-of-function mechanism explains the distinct genotype–phenotype correlations for skull and limb malformations. Rare individuals with Apert syndrome caused by distinct FGFR2 mutations are enumerated and the mechanisms underlying their phenotypic similarity to the canonical substitutions are presented. The germline rates for the two canonical mutations in FGFR2 (c.755C>G and c.758C>G) are among the highest in the human genome. The mutations arise exclusively from the unaffected father, exhibit a paternal age effect, and are attributable to “selfish” positive selection of mutant spermatogonial stem cells in the testis. The engineering of mouse mutants harboring genotypically equivalent Apert mutations helps to elucidate the developmental pathology of craniosynostosis and implicates activation of the RAS–MAP kinase pathway as a critical mediator of many clinical features of Apert syndrome. Approaches to targeted genetic or pharmacological therapies are discussed, although these will be challenging to implement given the early onset of pathogenesis in the embryo.