Duplication of GTF2I Results in Separation Anxiety in Mice and Humans

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.

Toward a deeper characterization of the social phenotype of Williams syndrome: The association between personality and social drive

“…This is in line with previous reports suggesting that the anxiety associated with WS is specifically non-social in nature, relating to, e.g., anticipation about upcoming events, with a striking absence in relation to social contexts, e.g., interacting with unfamiliar people (Pober, 2010). This also combines with a failure to demonstrate separation anxiety as children upon being separated from their parents in WS (Mervis et al, 2012). Recently, a neuroimaging study by Jabbi et al (2012) revealed that the neurogenetic basis of the hypersocial-anxious phenotype associated with WS implicates altered insula volume as well as aberrant connectivity between the insula and the amygdala and the OFC.…”

The social phenotype of Williams syndrome

“…The characteristic WS sociability may further be characterized by an attraction to strangers [4], a propensity to direct eye contact [13] and a bias toward focusing on the faces and eyes [14, 15], abnormally expressive language [16], a penchant for positive affect, evident in both receptive and expressive functions [5**, 17], and insensitivity to negative emotional signals [18], suggesting social fearlessness. The profound interest in unfamiliar people is observable from infancy (Figure 2), and is exhibited also by the lack of separation/stranger anxiety shown by children with WS when separated from their parents [19**]. …”

“…A recently identified 7q11.23 duplication syndrome is associated with separation anxiety disorder and/or social phobia; features that are not only typically absent, but contrary in individuals with WS [19**]. Interestingly, spontaneous duplication of the 7q11.23 has recently also been linked to autism [55*].…”

Pathophysiology of TFII-I: Old Guard Wearing New Hats

“…In individuals with smaller microdeletions sparing GTF2I , a WBS cognitive profile but no mental retardation or intellectual difficulties was identified (30). GTF2I is also likely to be involved in other neurobehavioral impairments of subjects with WBS (31–33). Notably, one study focused on rs13227433, which is a single nucleotide polymorphism (SNP) within the GTF2I gene that has shown a functional association with higher engagement in social interaction but reduced social abilities (34).…”