Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder.
Fiche publication
Date publication
décembre 2014
Journal
Human molecular genetics
Auteurs
Membres identifiés du Cancéropôle Est :
Dr HERAULT Yann
Tous les auteurs :
Segura-Puimedon M, Sahún I, Velot E, Dubus P, Borralleras C, Rodrigues AJ, Valero MC, Valverde O, Sousa N, Herault Y, Dierssen M, Pérez-Jurado LA, Campuzano V
Lien Pubmed
Résumé
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.
Mots clés
Animals, Behavior, Animal, Body Weight, Brain, pathology, Cardiomegaly, physiopathology, Chromosome Deletion, Chromosomes, Human, Pair 7, Chromosomes, Mammalian, Craniofacial Abnormalities, genetics, Disease Models, Animal, Female, Gene Dosage, Genes, Lethal, Heterozygote, Humans, Hypertension, physiopathology, Male, Mice, Mice, Knockout, Neurons, pathology, Organ Size, Synteny, Williams Syndrome, genetics
Référence
Hum. Mol. Genet.. 2014 Dec;23(24):6481-94