title: Alterations to the remote control of Shh gene expression cause congenital abnormalities.
abstract: Multi-species conserved non-coding elements occur in the vertebrate genome and are clustered in the vicinity of developmentally regulated genes. Many are known to act as cis-regulators of transcription and may reside at long distances from the genes they regulate. However, the relationship of conserved sequence to encoded regulatory information and indeed, the mechanism by which these contribute to long-range transcriptional regulation is not well understood. The ZRS, a highly conserved cis-regulator, is a paradigm for such long-range gene regulation. The ZRS acts over approximately 1 Mb to control spatio-temporal expression of Shh in the limb bud and mutations within it result in a number of limb abnormalities, including polydactyly, tibial hypoplasia and syndactyly. We describe the activity of this developmental regulator and discuss a number of mechanisms by which regulatory mutations in this enhancer function to cause congenital abnormalities.
authors: MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK. bob.hill@igmm.ed.ac.uk
authors: Robert E
authors: RE
authors: Hill
authors: Laura A
authors: LA
authors: Lettice
mesh_terms: D000818:Animals; D001665:Binding Sites; D000013:Congenital Abnormalities / Q000235:genetics* / Q000378:metabolism; D017124:Conserved Sequence; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics; D009154:Mutation; D014158:Transcription, Genetic
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse
keywords: Shh; limb development; long-range regulation; preaxial polydactyly
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