title: The disruption of a novel limb cis-regulatory element of SHH is associated with autosomal dominant preaxial polydactyly-hypertrichosis.
abstract: The expression gradient of the morphogen Sonic Hedgehog (SHH) is crucial in establishing the number and the identity of the digits during anteroposterior patterning of the limb. Its anterior ectopic expression is responsible for preaxial polydactyly (PPD). Most of these malformations are due to the gain-of-function of the Zone of Polarizing Activity Regulatory Sequence, the only limb-specific enhancer of SHH known to date. We report a family affected with a novel condition associating PPD and hypertrichosis of the upper back, following an autosomal dominant mode of inheritance. This phenotype is consistent with deregulation of SHH expression during limb and follicle development. In affected members, we identified a 2 kb deletion located ~240 kb upstream from the SHH promoter. The deleted sequence is capable of repressing the transcriptional activity of the SHH promoter in vitro, consistent with a silencer activity. We hypothesize that the deletion of this silencer could be responsible for SHH deregulation during development, leading to a PPD-hypertrichosis phenotype.
authors.affiliation: Centre de Référence Maladies Rares pour les syndromes malformatifs d'origine génétique, Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU, Lille, France.|RADEME (Research team on rare developmental and metabolic diseases), Université Lille 2, Lille, France.|Université Lille 2, Lille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Petit
authors.affiliation: RADEME (Research team on rare developmental and metabolic diseases), Université Lille 2, Lille, France.|Laboratoire de Biochimie et Biologie Moléculaire, Centre de Biologie-Pathologie, CHRU, Lille, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Jourdain
authors.affiliation: Université Lille 2, Lille, France.|Clinical Genetics Department, Guy's Hospital, London, UK.
authors.forename: Muriel
authors.initials: M
authors.lastname: Holder-Espinasse
authors.affiliation: Laboratoire de Cytogénétique, Groupe Hospitalier Pitié-Salpétrière, CHU, Paris, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Keren
authors.affiliation: RADEME (Research team on rare developmental and metabolic diseases), Université Lille 2, Lille, France.|Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU, Lille, France.
authors.forename: Joris
authors.initials: J
authors.lastname: Andrieux
authors.affiliation: Université Lille 2, Lille, France.|UMR8161 CNRS, Institut de Biologie de Lille, Institut Pasteur de Lille, Université Lille 1 et 2, IFR 142, Lille, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Duterque-Coquillaud
authors.affiliation: Université Lille 2, Lille, France.|Laboratoire de Biochimie et Biologie Moléculaire, Centre de Biologie-Pathologie, CHRU, Lille, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Porchet
authors.affiliation: Centre de Référence Maladies Rares pour les syndromes malformatifs d'origine génétique, Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU, Lille, France.|RADEME (Research team on rare developmental and metabolic diseases), Université Lille 2, Lille, France.|Université Lille 2, Lille, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Manouvrier-Hanu
authors.affiliation: RADEME (Research team on rare developmental and metabolic diseases), Université Lille 2, Lille, France.|Laboratoire de Biochimie et Biologie Moléculaire, Centre de Biologie-Pathologie, CHRU, Lille, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Escande
mesh_terms: D020121:5' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D019521:Body Patterning / Q000235:genetics; D002648:Child; D005260:Female; D005385:Fingers / Q000002:abnormalities; D018507:Gene Expression Regulation, Developmental; D005799:Genes, Dominant; D006239:Haplotypes; D053823:Hedgehog Proteins / Q000235:genetics*; D006801:Humans; D006983:Hypertrichosis / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D017689:Polydactyly / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D037941:Silencer Elements, Transcriptional; D044465:White People
chemical_list: D020121:5' Untranslated Regions; D053823:Hedgehog Proteins; C509239:SHH protein, human