Skulls, limbs and sperm: common themes in malformation. (360G-Wellcome-078666_Z_05_Z)

This proposal explores the surprising biological links between development of the skull and limbs, and the biology of spermatogenesis, through a combinationof human studies and mouse models. Focusing on two groups of signalling molecules, the fibroblast growth factor receptors (FGFRs) and ephrins, we aim to identify new causes of skull and limb malformation, evaluate a new approachto the clinical classification of craniosynostosis using microarrays, investigate allelic modifiers of gene expression, and probe the unexplored biology of selective advantage of mutations during male spermatogenesis through further studies of FGFR mutations in sperm and testes. Specific goals include:1. Screening for relevant mutations in human craniosynostosis and limbmalformations.2. Identification of gene expression signatures in patients withcraniosynostosis.3. Understanding the pathogenesis of two common genetic causes of craniosynostosis, using mouse disease models. 4. Description of mechanisms and consequences of allelic bias in FGFR2 expression.5. Descriptionof mutation dynamics of FGFR2 and other genes in sperm and testes.This programme of work represents a critical contribution to international efforts to improve genetic diagnosis and counselling in these disorders.