title: Molecular basis of imprinting disorders affecting chromosome 14: lessons from murine models.
abstract: Uniparental inheritance of chromosome 14q32 causes developmental failure during gestation and early postnatal development due to mis-expression of a cluster of imprinted genes under common epigenetic control. Two syndromes associated with chromosome 14q32 abnormalities have been described, Kagami-Ogata and Temple syndromes. Both of these syndromes are characterised by specific impairments of intrauterine development, placentation and early postnatal survival. Such abnormalities arise because the processes of intrauterine growth and postnatal adaptation are critically modulated by the dosage of imprinted genes in the chromosome 14q32 cluster. Much of our understanding of how the imprinted genes in this cluster are regulated, as well as their individual functions in the molecular pathways controlling growth and postnatal adaptation, has come from murine models. Mouse chromosome 12qF1 contains an imprinted region syntenic to human chromosome 14q32, collectively referred to as the Dlk1-Dio3 cluster. In this review, we will summarise the wealth of information derived from animal models of chromosome 12 imprinted gene mis-regulation, and explore the relationship between the functions of individual genes and the phenotypic result of their mis-expression. As there is often a considerable overlap between the functions of genes in the Dlk1-Dio3 cluster, we propose that the expression dosage of these genes is controlled by common regulatory mechanisms to co-ordinate the timing of growth and postnatal adaptation. While the diseases associated with mis-regulated chromosome 14 imprinting are rare, studies carried out in mice on the functions of the affected genes as well as their normal regulatory mechanisms have revealed new mechanistic pathways for the control of growth and survival in early life.
authors.affiliation: Barts and The London School of Medicine and DentistryWilliam Harvey Research Institute, Centre for Endocrinology, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Howard
authors.affiliation: Barts and The London School of Medicine and DentistryWilliam Harvey Research Institute, Centre for Endocrinology, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK m.charalambous@qmul.ac.uk.
authors.forename: Marika
authors.initials: M
authors.lastname: Charalambous
mesh_terms: D000818:Animals; D025063:Chromosome Disorders / Q000235:genetics*; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D018392:Genomic Imprinting; D006801:Humans; D051379:Mice