title: Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder.
abstract: Williams-Beuren syndrome is a developmental multisystemic disorder caused by a recurrent 1.55-1.83 Mb heterozygous deletion on human chromosome band 7q11.23. Through chromosomal engineering with the cre-loxP system, we have generated mice with an almost complete deletion (CD) of the conserved syntenic region on chromosome 5G2. Heterozygous CD mice were viable, fertile and had a normal lifespan, while homozygotes were early embryonic lethal. Transcript levels of most deleted genes were reduced 50% in several tissues, consistent with gene dosage. Heterozygous mutant mice showed postnatal growth delay with reduced body weight and craniofacial abnormalities such as small mandible. The cardiovascular phenotype was only manifested with borderline hypertension, mildly increased arterial wall thickness and cardiac hypertrophy. The neurobehavioral phenotype revealed impairments in motor coordination, increased startle response to acoustic stimuli and hypersociability. Mutant mice showed a general reduction in brain weight. Cellular and histological abnormalities were present in the amygdala, cortex and hippocampus, including increased proportion of immature neurons. In summary, these mice recapitulate most crucial phenotypes of the human disorder, provide novel insights into the pathophysiological mechanisms of the disease such as the neural substrates of the behavioral manifestations, and will be valuable to evaluate novel therapeutic approaches.
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08003, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Segura-Puimedon
authors.affiliation: Laboratory Animal Applied Research Platform (PRAAL), Barcelona 08028, Spain.
authors.forename: Ignasi
authors.initials: I
authors.lastname: Sahún
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Translational Medicine and Neuroscience, Centre National de la Recherche Scientifique, CNRS UMR7104, Institut National de la Santé et de la Recherche Médicale, INSERM U964, Université de Strasbourg, Institut Clinique de la Souris, ICS, PHENOMIN, GIE CERBM, Illkirch CEDEX 67404, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Velot
authors.affiliation: EA2406, University of Bordeaux, Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Spain, Neurosciences Program, Institut Hospital del Mar D'Investigacions Mèdiques (IMIM), Barcelona 08003, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Borralleras
authors.affiliation: Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, and ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Rodrigues
authors.affiliation: Department of Entomology, University of Illinois, Urbana Champaign, IL 61801, USA and.
authors.forename: María C
authors.initials: MC
authors.lastname: Valero
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08003, Spain, Neurosciences Program, Institut Hospital del Mar D'Investigacions Mèdiques (IMIM), Barcelona 08003, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Valverde
authors.affiliation: Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, and ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Sousa
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Translational Medicine and Neuroscience, Centre National de la Recherche Scientifique, CNRS UMR7104, Institut National de la Santé et de la Recherche Médicale, INSERM U964, Université de Strasbourg, Institut Clinique de la Souris, ICS, PHENOMIN, GIE CERBM, Illkirch CEDEX 67404, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Herault
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Spain, Neurosciences Program, Institut Hospital del Mar D'Investigacions Mèdiques (IMIM), Barcelona 08003, Spain, Centre de Regulació Genòmica (CRG), Barcelona 08003, Spain.
authors.forename: Mara
authors.initials: M
authors.lastname: Dierssen
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08003, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Spain, Neurosciences Program, Institut Hospital del Mar D'Investigacions Mèdiques (IMIM), Barcelona 08003, Spain.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Pérez-Jurado
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08003, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Spain, Neurosciences Program, Institut Hospital del Mar D'Investigacions Mèdiques (IMIM), Barcelona 08003, Spain, victoria.campuzano@upf.edu.
authors.forename: Victoria
authors.initials: V
authors.lastname: Campuzano
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D006332:Cardiomegaly / Q000503:physiopathology; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7; D033481:Chromosomes, Mammalian; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D018628:Gene Dosage; D005804:Genes, Lethal; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology; D009929:Organ Size; D026801:Synteny; D018980:Williams Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology