title: Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly.
abstract: Preaxial polydactyly (PPD) is a common limb malformation in human. A number of polydactylous mouse mutants indicate that misexpression of Shh is a common requirement for generating extra digits. Here we identify a translocation breakpoint in a PPD patient and a transgenic insertion site in the polydactylous mouse mutant sasquatch (Ssq). The genetic lesions in both lie within the same respective intron of the LMBR1/Lmbr1 gene, which resides approximately 1 Mb away from Shh. Genetic analysis of Ssq reveals that the Lmbr1 gene is incidental to the phenotype and that the mutation directly interrupts a cis-acting regulator of Shh. This regulator is most likely the target for generating PPD mutations in human.
authors.affiliation: Medical Research Council Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Lettice
authors.forename: Taizo
authors.initials: T
authors.lastname: Horikoshi
authors.forename: Simon J H
authors.initials: SJ
authors.lastname: Heaney
authors.forename: Marijke J
authors.initials: MJ
authors.lastname: van Baren
authors.forename: Herma C
authors.initials: HC
authors.lastname: van der Linde
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Breedveld
authors.forename: Marijke
authors.initials: M
authors.lastname: Joosse
authors.forename: Nurten
authors.initials: N
authors.lastname: Akarsu
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Naoto
authors.initials: N
authors.lastname: Endo
authors.forename: Minoru
authors.initials: M
authors.lastname: Shibata
authors.forename: Mikio
authors.initials: M
authors.lastname: Suzuki
authors.forename: Eiichi
authors.initials: E
authors.lastname: Takahashi
authors.forename: Toshikatsu
authors.initials: T
authors.lastname: Shinka
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakahori
authors.forename: Dai
authors.initials: D
authors.lastname: Ayusawa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakabayashi
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hill
authors.forename: Sumihare
authors.initials: S
authors.lastname: Noji
mesh_terms: D000818:Animals; D003001:Cloning, Molecular; D003433:Crosses, Genetic; D053823:Hedgehog Proteins; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007438:Introns; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D010641:Phenotype; D017689:Polydactyly / Q000235:genetics*; D011995:Recombination, Genetic; D015183:Restriction Mapping; D015534:Trans-Activators / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D053823:Hedgehog Proteins; C485955:LMBR1 protein, human; C417920:Lmbr1 protein, mouse; D008565:Membrane Proteins; C509239:SHH protein, human; D015534:Trans-Activators