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Gtf2i and Gtf2ird1 mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region

Nathan Kopp, Katherine McCullough, Susan E. Maloney, View ORCID ProfileJoseph D. Dougherty
doi: https://doi.org/10.1101/558544
Nathan Kopp
1Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
2Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
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Katherine McCullough
1Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
2Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
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Susan E. Maloney
2Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
3Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO, USA
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Joseph D. Dougherty
1Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
2Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
3Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO, USA
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  • ORCID record for Joseph D. Dougherty
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Abstract

Williams syndrome is a neurodevelopmental disorder caused by a 1.5-1.8Mbp deletion on chromosome 7q11.23, affecting the copy number of 26-28 genes. Phenotypes of Williams syndrome include cardiovascular problems, craniofacial dysmorphology, deficits in visual spatial cognition, and a characteristic hypersocial personality. There are still no genes in the region that have been consistently linked to the cognitive and behavioral phenotypes, although human studies and mouse models have led to the current hypothesis that the general transcription factor 2 I family of genes, GTF2I and GTF2IRD1, are responsible. Here we test the hypothesis that these two transcription factors are sufficient to reproduce the phenotypes that are caused by deletion of the Williams syndrome critical region (WSCR). We compare a new mouse model with loss of function mutations in both Gtf2i and Gtf2ird1 to an established mouse model lacking the complete WSCR. We show that the complete deletion model has deficits across several behavioral domains including social communication, motor functioning, and conditioned fear that are not explained by loss of function mutations in Gtf2i and Gtf2ird1. Furthermore, transcriptome profiling of the hippocampus shows changes in synaptic genes in the complete deletion model that are not seen in the double mutants. Thus, we have thoroughly defined a set of molecular and behavioral consequences of complete WSCR deletion, and shown that other genes or combinations of genes are necessary to produce these phenotypic effects.

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Posted February 24, 2019.
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Gtf2i and Gtf2ird1 mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region
Nathan Kopp, Katherine McCullough, Susan E. Maloney, Joseph D. Dougherty
bioRxiv 558544; doi: https://doi.org/10.1101/558544
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Gtf2i and Gtf2ird1 mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region
Nathan Kopp, Katherine McCullough, Susan E. Maloney, Joseph D. Dougherty
bioRxiv 558544; doi: https://doi.org/10.1101/558544

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