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. 2012 Jun 8;90(6):1064-70.
doi: 10.1016/j.ajhg.2012.04.012. Epub 2012 May 10.

Duplication of GTF2I results in separation anxiety in mice and humans

Carolyn B Mervis  1 , Joana Dida, Emily Lam, Nicole A Crawford-Zelli, Edwin J Young, Danielle R Henderson, Tuncer Onay, Colleen A Morris, Janet Woodruff-Borden, John Yeomans, Lucy R Osborne
Affiliations

Duplication of GTF2I results in separation anxiety in mice and humans

Carolyn B Mervis et al. Am J Hum Genet. .

Abstract

Duplication (dup7q11.23) and deletion (Williams syndrome) of chromosomal region 7q11.23 cause neurodevelopmental disorders with contrasting anxiety phenotypes. We found that 30% of 4- to 12-year-olds with dup7q11.23 but fewer than 5% of children with WS or in the general population met diagnostic criteria for a separation-anxiety disorder. To address the role of one commonly duplicated or deleted gene in separation anxiety, we compared mice that had varying numbers of Gtf2i copies. Relative to mouse pups with one or two Gtf2i copies, pups with additional Gtf2i copies showed significantly increased maternal separation-induced anxiety as measured by ultrasonic vocalizations. This study links the copy number of a single gene from 7q11.23 to separation anxiety in both mice and humans, highlighting the utility of mouse models in dissecting specific gene functions for genomic disorders that span many genes. This study also offers insight into molecular separation-anxiety pathways that might enable the development of targeted therapeutics.

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Figures

Figure 1
Figure 1
Generation of Mice with Decreased or Increased Gtf2i Dosage (A) Schematic representation of the generation of mice with duplication of Gtf2i. XS0608 contains a loxP site inserted into intron 4 of Gtf2ird1, whereas the 3′UTR-loxP line contains a loxP site downstream of the last coding exon of Gtf2i. Recombination between the loxP sites in vivo resulted in duplication of the entire Gtf2i gene in the male gamete of transloxer male mice carrying both loxP sites in trans, as well as a Cre transgene under the control of the Sycp1 promoter. Duplicated chromosomes were transmitted to offspring upon crossing with wild-type (WT) females. The centromere of mouse chromosome 5 is represented by the circle at the left end of each diagram. LoxP sites are represented by a shaded triangle. (B) Immunoblot analysis of GTF2I from whole brain of P8 mice with the use of a polyclonal antibody (610943, BD Biosciences, Franklin Lakes, NJ). GAPDH (ab36840, Abcam, Cambridge, MA) was used as a control for protein loading (50 μg per lane). Representative blots from three independent pups are shown. (C) A graph (created with Image J [National Institutes of Health]) comparing the densitometric measurement of GAPDH with that of GTF2I in whole brain of P8 mice. Data are represented as mean ± SEM (n = 3 for each group).
Figure 2
Figure 2
Number of USVs Produced by Mouse Pups during Maternal-Separation Period (A) Box plots show the distribution of USVs produced over the 4 min testing period as a function of genotype. Data are represented as the median plus the upper and lower quartiles. The lowest and highest observations are indicated by whiskers. The outlier is indicated by an asterisk. (B) Median number of USVs produced by P8 mouse pups during each minute of the 4 min maternal-separation period as a function of genotype.
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