title: Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus.
abstract: The study of homeotic-transformation mutants in model organisms such as Drosophila revolutionized the field of developmental biology, but how these mutants relate to human developmental defects remains to be elucidated. Here, we show that Liebenberg syndrome, an autosomal-dominant upper-limb malformation, shows features of a homeotic limb transformation in which the arms have acquired morphological characteristics of a leg. Using high-resolution array comparative genomic hybridization and paired-end whole-genome sequencing, we identified two deletions and a translocation 5' of PITX1. The structural changes are likely to remove active PITX1 forelimb suppressor and/or insulator elements and thereby move active enhancer elements in the vicinity of the PITX1 regulatory landscape. We generated transgenic mice in which PITX1 was misexpressed under the control of a nearby enhancer and were able to recapitulate the Liebenberg phenotype.
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Spielmann
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.forename: Peter M
authors.initials: PM
authors.lastname: Krawitz
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Ibrahim
authors.forename: Martin
authors.initials: M
authors.lastname: Franke
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.forename: Silke
authors.initials: S
authors.lastname: Lohan
authors.forename: Katarina
authors.initials: K
authors.lastname: Dathe
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Nardone
authors.forename: Paola
authors.initials: P
authors.lastname: Ferrari
authors.forename: Antonio
authors.initials: A
authors.lastname: Landi
authors.forename: Lars
authors.initials: L
authors.lastname: Wittler
authors.forename: Bernd
authors.initials: B
authors.lastname: Timmermann
authors.forename: Danny
authors.initials: D
authors.lastname: Chan
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mennen
authors.forename: Eva
authors.initials: E
authors.lastname: Klopocki
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
mesh_terms: D000818:Animals; D059327:Brachydactyly / Q000235:genetics*; D002348:Carpal Bones / Q000002:abnormalities; D055028:Comparative Genomic Hybridization / Q000379:methods; D004551:Elbow Joint / Q000002:abnormalities; D005260:Female; D005385:Fingers / Q000002:abnormalities; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D015321:Gene Rearrangement; D005801:Genes, Homeobox; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006228:Hand Deformities, Congenital / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051761:Paired Box Transcription Factors / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D013580:Synostosis / Q000235:genetics*; D014170:Transformation, Genetic; D014178:Translocation, Genetic; D014955:Wrist Joint / Q000002:abnormalities
chemical_list: D051761:Paired Box Transcription Factors; C101485:homeobox protein PITX1