TY - JOUR
T1 - Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder
AU - Segura-Puimedon, Maria
AU - Sahún, Ignasi
AU - Velot, Emilie
AU - Dubus, Pierre
AU - Borralleras, Cristina
AU - Rodrigues, Ana J.
AU - Valero, María C.
AU - Valverde, Olga
AU - Sousa, Nuno
AU - Herault, Yann
AU - Dierssen, Mara
AU - Pérez-Jurado, Luis A.
AU - Campuzano, Victoria
N1 - Publisher Copyright:
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].
PY - 2014/12/15
Y1 - 2014/12/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84930629892&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddu368
DO - 10.1093/hmg/ddu368
M3 - Article
C2 - 25027326
AN - SCOPUS:84930629892
SN - 0964-6906
VL - 23
SP - 6481
EP - 6494
JO - Human molecular genetics
JF - Human molecular genetics
IS - 24
ER -