Consistent hypersocial behavior in mice carrying a deletion of <i>Gtf2i</i> but no evidence of hyposocial behavior with <i>Gtf2i</i> duplication: Implications for Williams–Beuren syndrome and autism spectrum disorder

Martin, Loren A.; Iceberg, Erica; Allaf, Gabriel

doi:10.1002/brb3.895

Cited by 15 publications

(9 citation statements)

References 49 publications

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“…Behavioral phenotyping of the A350V IQSEC2 mice demonstrates increased locomotion, abnormal social interactions and learning impairments in the absence of motor coordination deficits. The increased preference for social novelty in the A350V mice described here, while different from what has been described in autism, has been described in other genetic encephalopathies with intellectual disability and abnormal social functioning such as Williams’s syndrome (Martin et al, 2018; Ng et al, 2018). Our behavioral findings in the A350V mice appear to model some of the abnormal behaviors found in the human index case with the A350V mutation, specifically hyperactivity, abnormal social interactions with no inhibitions with strangers and impaired cognitive function.…”

Section: Discussionsupporting

confidence: 44%

An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

Rogers

Jada

Schragenheim-Rozales

et al. 2019

Front. Mol. Neurosci.

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We have recently described an A350V mutation in IQSEC2 associated with intellectual disability, autism and epilepsy. We sought to understand the molecular pathophysiology of this mutation with the goal of developing targets for drug intervention. We demonstrate here that the A350V mutation results in interference with the binding of apocalmodulin to the IQ domain of IQSEC2. We further demonstrate that this mutation results in constitutive activation of the guanine nucleotide exchange factor (GEF) activity of IQSEC2 resulting in increased production of the active form of Arf6. In a CRISPR generated mouse model of the A350V IQSEC2 mutation, we demonstrate that the surface expression of GluA2 AMPA receptors in mouse hippocampal tissue was significantly reduced in A350V IQSEC2 mutant mice compared to wild type IQSEC2 mice and that there is a significant reduction in basal synaptic transmission in the hippocampus of A350V IQSEC2 mice compared to wild type IQSEC2 mice. Finally, the A350V IQSEC2 mice demonstrated increased activity, abnormal social behavior and learning as compared to wild type IQSEC2 mice. These findings suggest a model of how the A350V mutation in IQSEC2 may mediate disease with implications for targets for drug therapy. These studies provide a paradigm for a personalized approach to precision therapy for a disease that heretofore has no therapy.

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Section: Discussionsupporting

confidence: 44%

An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

Rogers

Jada

Schragenheim-Rozales

et al. 2019

Front. Mol. Neurosci.

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“…GTF2I gene encodes transcription factor TFII‐I, which acts as an inducible multifunctional transcription factor in the nucleus (Danoff, Taylor, Blackshaw, & Desiderio, ; Roy, ) and as a regulator of agonist‐induced calcium entry in the cytoplasm (Caraveo et al., ). Loss of GTF2I led to a negative effect on neurocognitive and behavioral profiles (Chailangkarn, Noree, & Muotri, ; Martin, Iceberg, & Allaf, ; Morris et al., ), but prenatal assessment of functional lesions is not possible. NCF1 gene encodes a component of the NADPH oxidase complex.…”

Section: Discussionmentioning

confidence: 99%

Intrauterine phenotype features of fetuses with Williams–Beuren syndrome and literature review

Yuan

Deng

Yang

et al. 2019

Annals of Human Genetics

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Williams-Beuren syndrome (WBS) is a well-defined multisystem chromosomal disorder that is caused by a chromosome 7q11.23 region heterozygous deletion. We explored prenatal diagnosis of WBS by ultrasound as well as multiple genetic methods to characterize the structural variants of WBS prenatally. Expanded noninvasive prenatal testing (NIPT-plus) was elected as a regular prenatal advanced screen for risk assessments of fetal chromosomal aneuploidy and genome-wide microdeletion/microduplication syndromes at the first trimester. At the second and three trimester, seven prenatal cases of WBS were evaluated for the indication of the invasive testing, the ultrasound features, cytogenetic, single-nucleotide polymorphism array (SNP array), and fluorescent quantitative PCR (QF-PCR) results. The NIPTplus results for seven fetuses were low risk. All cryptic aberrations were detected by the SNP array as karyotyping analyses were negative. Subsequently, QF-PCR further confirmed the seven deletions. Combining our cases with 10 prenatal cases from the literature, the most common sonographic features were intrauterine growth retardation (82.35%, 14/17) and congenital cardiovascular abnormalities (58.82%, 10/17).The manifestations of cardiovascular defects mainly involve supravalvar aortic stenosis (40%, 4/10), ventricular septal defect (30%, 3/10), aortic coarctation (20%, 2/10), and peripheral pulmonary artery stenosis (20%, 2/10). To the best of our knowledge, this is the first largest prenatal study of WBS cases with detailed molecular analysis. Aortic coarctation combined with persistent left superior vena cava and right aortic arch cardiovascular defects were first reported in prenatal WBS cases by our study.

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“…Mouse models that are haploinsufficient for only Gtf2i have shown in the three-chamber approach task that after eight minutes WT animals investigate a novel object the same amount as a social stimulus, but the Gtf2i mutants still have a significant preference suggesting a lack of habituation (33). In another Gtf2i model, Martin et al compared animals with one, two, three, and four copies of Gtf2i in the three-chamber social approach task, and showed that only animals with one and three copies of Gtf2i displayed a significant preference for the social stimulus (36), but WT animals did not. These three-chamber social approach tests are interpreting a lack of significance as evidence for increased social behavior and not directly comparing the levels of investigation between genotypes (52).…”

Section: Discussionmentioning

confidence: 99%

“…For example, newer tasks, such as social operant tasks that test motivation to receive a social stimulus may more directly test the aspects of social behavior that are affected in WS. This task has been performed on Gtf2i mutants and mice that have only one copy of Gtf2i will work harder to receive a social reward (36).…”

Section: Discussionmentioning

confidence: 99%

“…Direct social tasks have higher heritability than the three-chamber social approach and offer a more natural social experience (53), which may make them a more sensitive assay for testing social behaviors. Direct tasks have shown that Gtf2i models have increased nose-to-nose investigation time (36), mouse models lacking the proximal end of the region have increased investigation frequency (29), and Gtf2ird1 mutants make fewer aggressive actions but show increased following time (30). We employed the resident-intruder paradigm as a full contact social assay.…”

Section: Discussionmentioning

confidence: 99%

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

Kopp¹,

McCullough²,

Se³

et al. 2019

Preprint

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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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Consistent hypersocial behavior in mice carrying a deletion of Gtf2i but no evidence of hyposocial behavior with Gtf2i duplication: Implications for Williams–Beuren syndrome and autism spectrum disorder

Cited by 15 publications

References 49 publications

An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

Intrauterine phenotype features of fetuses with Williams–Beuren syndrome and literature review

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

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