Transcriptional dysregulation in skeletal malformation syndromes

Normal skeletal development requires coordinated temporal and spatial gene expression patterns that specify the functions of various cell types. Transcription factors by definition coordinate this process and are themselves subject to hierarchical levels of regulation. Together they determine the context-dependent function of each transcription factor. Hence, loss-of-function and gain-of-function mutations within specific transcription factors cause dysregulation of broad transcriptional networks. Consequences are usually dominantly inherited skeletal malformation syndromes that can be broadly viewed as consequences of defects of cellular differentiation, proliferation, and survival versus defects in pattern formation. The study of human phenotypes and mutations can lead to hypotheses about targets within the respective transcriptional network. These targets can then be confirmed by combining mouse genetic and in vitro studies. Although this has been successful in a small group of skeletal dysplasias, the majority of transcriptional networks during skeletogenesis remain to be elucidated.