Haploinsufficiency of Gtf2i, a gene deleted in Williams Syndrome, leads to increases in social interactions

Authors

  • Takeshi Sakurai,

    1. Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, New York
    2. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York
    3. Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York
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  • Nathan P. Dorr,

    1. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York
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  • Nagahide Takahashi,

    1. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York
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  • L. Alison McInnes,

    1. Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, New York
    2. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York
    Current affiliation:
    1. Department of Psychiatry, San Francisco Medical Center, San Francisco, CA 94118
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  • Gregory A. Elder,

    1. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York
    2. Department of Neurology, Mount Sinai School of Medicine, New York, New York
    3. Neurology Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, New York
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  • Joseph D. Buxbaum

    Corresponding author
    1. Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, New York
    2. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York
    3. Department of Neuroscience, Mount Sinai School of Medicine, New York, New York
    4. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York
    • Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1668, New York, New York 10029
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Abstract

Identifying genes involved in social behavior is important for autism research. Williams–Beuren syndrome (WBS) is a developmental syndrome with unique neurocognitive features, including low IQ, deficits in visuospatial and visual-motor abilities, hypersensitivity to sounds, hypersociability, and increased general anxiety. The syndrome is caused by a recurrent hemizygous deletion of the 7q11.23 region, containing about 28 genes. One of genes in the region, GTF2I, has been implicated in the hypersociability and visuospatial deficits of WBS based on genotype–phenotype correlation studies of patients with atypical deletions. In order to clarify the involvement of GTF2I in neurocognitive function, especially social behavior, we have developed and characterized Gtf2i-deficient mice. We found that homozygous deletion of Gtf2i causes lethality during embryonic development with neural tube closure defects and exencephaly, consistent with other reports. Gtf2i heterozygous animals show no gross changes in brain structure or development. Furthermore, heterozygous animals show no alterations in learning and memory, including spatial memory as assessed by the Morris water maze, but show alterations in the recognition of novel objects. Interestingly, they show increased social interaction with unfamiliar mice and do not show typical social habituation processes, reminiscent of the hypersociability observed in WBS patients. The mice do not appear to show increased anxiety, supporting a specific effect of Gtf2i on defined domains of the WBS phenotype. These data indicate that Gtf2i is involved in several aspects of embryonic development and the development of social neurocircuitry and that GTF2I haploinsufficiency could be a contributor to the hypersociability in WBS patients.

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