title: Enhancer-adoption as a mechanism of human developmental disease.
abstract: Disruption of the long-range cis-regulation of developmental gene expression is increasingly recognized as a cause of human disease. Here, we report a novel type of long-range cis-regulatory mutation, in which ectopic expression of a gene is driven by an enhancer that is not its own. We have termed this gain of regulatory information as "enhancer adoption." We mapped the breakpoints of a de novo 7q inversion in a child with features of a holoprosencephaly spectrum (HPES) disorder and severe upper limb syndactyly with lower limb synpolydactyly. The HPES plausibly results from the 7q36.3 breakpoint dislocating the sonic hedgehog (SHH) gene from enhancers that are known to drive expression in the early forebrain. However, the limb phenotype cannot be explained by loss of known SHH enhancers. The SHH transcription unit is relocated to 7q22.1, ∼190 kb 3' of a highly conserved noncoding element (HCNE2) within an intron of EMID2. We show that HCNE2 functions as a limb bud enhancer in mouse embryos and drives ectopic expression of Shh in vivo recapitulating the limb phenotype in the child. This developmental genetic mechanism may explain a proportion of the novel or unexplained phenotypes associated with balanced chromosome rearrangements.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh. laura.lettice@hgu.mrc.ac.uk
authors.forename: Laura A
authors.initials: LA
authors.lastname: Lettice
authors.forename: Sarah
authors.initials: S
authors.lastname: Daniels
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sweeney
authors.forename: Shanmugasundaram
authors.initials: S
authors.lastname: Venkataraman
authors.forename: Paul S
authors.initials: PS
authors.lastname: Devenney
authors.forename: Philippe
authors.initials: P
authors.lastname: Gautier
authors.forename: Harris
authors.initials: H
authors.lastname: Morrison
authors.forename: Judy
authors.initials: J
authors.lastname: Fantes
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hill
authors.forename: David R
authors.initials: DR
authors.lastname: FitzPatrick
mesh_terms: D000818:Animals; D002675:Child, Preschool; D007446:Chromosome Inversion / Q000235:genetics*; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005121:Extremities / Q000196:embryology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D016142:Holoprosencephaly / Q000235:genetics*; D006801:Humans; D018878:Limb Buds / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D013576:Syndactyly / Q000235:genetics*
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human