Induced chromosome deletions cause hypersociability and other features of Williams–Beuren syndrome in mice

Li, Hong Hua; Roy, Michael S.; Kuscuoglu, Unsal; Spencer, Corinne M.; Halm, Birgit; Harrison, Katharine C.; Bayle, J. Henri; Splendore, Alessandra; Ding, Feng; Meltzer, Leslie A.; Wright, Elena; Paylor, Richard; Deisseroth, Karl; Francke, Uta

doi:10.1002/emmm.200900003

Cited by 97 publications

(132 citation statements)

References 56 publications

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“…This dominantnegative explanation predicts that heterozygous mutants would have more severe consequences than a hemizygous Gtf2ird1 deletion. This does appear to be the case, as some of the gene-trap mutants show more severe abnormalities than another recently reported mouse line in which 7 contiguous genes including Gtf2ird1 are hemizygously deleted (28).…”

Section: Discussionmentioning

confidence: 76%

Negative Autoregulation of GTF2IRD1 in Williams-Beuren Syndrome via a Novel DNA Binding Mechanism

Palmer

Santucci

Widagdo

et al. 2010

Journal of Biological Chemistry

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The GTF2IRD1 gene is of principal interest to the study of Williams-Beuren syndrome (WBS). This neurodevelopmental disorder results from the hemizygous deletion of a region of chromosome 7q11.23 containing 28 genes including GTF2IRD1. WBS is thought to be caused by haploinsufficiency of certain dosage-sensitive genes within the deleted region, and the feature of supravalvular aortic stenosis (SVAS) has been attributed to reduced elastin caused by deletion of ELN. Human genetic mapping data have implicated two related genes GTF2IRD1 and GTF2I in the cause of some the key features of WBS, including craniofacial dysmorphology, hypersociability, and visuospatial deficits. Mice with mutations of the Gtf2ird1 allele show evidence of craniofacial abnormalities and behavioral changes. Here we show the existence of a negative autoregulatory mechanism that controls the level of GTF2IRD1 transcription via direct binding of the GTF2IRD1 protein to a highly conserved region of the GTF2IRD1 promoter containing an array of three binding sites. The affinity for this protein-DNA interaction is critically dependent upon multiple interactions between separate domains of the protein and at least two of the DNA binding sites. This autoregulatory mechanism leads to dosage compensation of GTF2IRD1 transcription in WBS patients. The GTF2IRD1 promoter represents the first established in vivo gene target of the GTF2IRD1 protein, and we use it to model its DNA interaction capabilities. Williams-Beuren syndrome (WBS)4 is a relatively rare disorder with an estimated incidence of 1:7,500 -1:20,000 (1). In 95% of cases, this deletion is 1.5 Mb long and results from illegitimate recombination during meiosis between two blocks of low copy repeats (LCRs) that flank the deletion domain (2, 3). To explain the causes of WBS in molecular terms, it is first necessary to identify the genes that underpin each of the disorders. The only symptom that fulfills this to date is SVAS. Haploinsufficiency of elastin due to loss of the ELN gene leads to narrowing of the large elastic aorta and may also affect the pulmonary, coronary, and carotid arteries (4). Accumulating evidence from patients with atypical hemizygous deletions within the critical region indicate that the many of the remaining symptoms, in particular the craniofacial abnormalities, the visuospatial construction deficit and the hypersociability, can be attributed to two genes at the telomeric end of the deletion region, GTF2IRD1 and GTF2I (5-7). These genes share sequence homology and are adjacent, indicating that they have arisen by duplication and divergence from a common ancestor. Functional evidence suggests that these genes encode nuclear proteins with DNA binding capabilities and are widely considered to be transcription factors with specific gene targets (8, 9).The first reported gene product of GTF2IRD1 was Mus-TRD1, which was isolated in a yeast one-hybrid screen for proteins that could bind to a DNA enhancer element present in the TNNI1 gene (10). Human, mouse, and Xenopus orthologs o...

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Section: Discussionmentioning

confidence: 76%

Negative Autoregulation of GTF2IRD1 in Williams-Beuren Syndrome via a Novel DNA Binding Mechanism

Palmer

Santucci

Widagdo

et al. 2010

Journal of Biological Chemistry

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“…Additionally, certain do- mains of behavior, such as social interaction and empathy for others, are even enhanced in these patients (2-6, 31, 49). One strategy to unravel the complexity of WS is to use genetically altered mice that have defined alterations in one or more of these genes (16,50). To this end, we have previously generated LIMK1 Ϫ/Ϫ mice and shown that these mice are altered in learning and memory (14,25).…”

Section: Discussionmentioning

confidence: 99%

LIMK1 Regulates Long-Term Memory and Synaptic Plasticity via the Transcriptional Factor CREB

Todorovski

Asrar

Liu

et al. 2015

Molecular and Cellular Biology

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e Deletion of the LIMK1 gene is associated with Williams syndrome, a unique neurodevelopmental disorder characterized by severe defects in visuospatial cognition and long-term memory (LTM). However, whether LIMK1 contributes to these deficits remains elusive. Here, we show that LIMK1-knockout (LIMK1 ؊/؊ ) mice are drastically impaired in LTM but not short-term memory (STM). In addition, LIMK1؊/؊ mice are selectively defective in late-phase long-term potentiation (L-LTP), a form of long-lasting synaptic plasticity specifically required for the formation of LTM. Furthermore, we show that LIMK1 interacts and regulates the activity of cyclic AMP response element-binding protein (CREB), an extensively studied transcriptional factor critical for LTM. Importantly, both L-LTP and LTM deficits in LIMK1 ؊/؊ mice are rescued by increasing the activity of CREB. These results provide strong evidence that LIMK1 deletion is sufficient to lead to an LTM deficit and that this deficit is attributable to CREB hypofunction. Our study has identified a direct gene-phenotype link in mice and provides a potential strategy to restore LTM in patients with Williams syndrome through the enhancement of CREB activity in the adult brain.

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“…Although the most remarkable abnormalities in craniofacial development are observed for mice lacking the entire WBS syntenic region, 28 mice lacking the human proximal region spanning Trim50:Limk1 (that includes Baz1b) showed only very mild facial defects. On the contrary, no differences in cranial morphology were reported in mice lacking the human distal region (Limk1:Gtf2i), in contrast to reported cases of individuals with atypical deletions that postulate a role for the most WBSCR distal genes as involved in the craniofacial phenotype.…”

Section: Patient Wbs166mentioning

confidence: 99%

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits

et al. 2013

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syndrome (WBS) is a multisystemic disorder caused by a hemizygous deletion of 1.5 Mb on chromosome 7q11.23 spanning 28 genes. A few patients with larger and smaller WBS deletion have been reported. They show clinical features that vary between isolated SVAS to the full spectrum of WBS phenotype, associated with epilepsy or autism spectrum behavior. Here we describe four patients with atypical WBS 7q11.23 deletions. Two carry B3.5 Mb larger deletion towards the telomere that includes Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxigenase activation protein gamma (YWHAG) genes. Other two carry a shorter deletion of B1.2 Mb at centromeric side that excludes the distal WBS genes BAZ1B and FZD9. Along with previously reported cases, genotype-phenotype correlation in the patients described here further suggests that haploinsufficiency of HIP1 and YWHAG might cause the severe neurological and neuropsychological deficits including epilepsy and autistic traits, and that the preservation of BAZ1B and FZD9 genes may be related to mild facial features and moderate neuropsychological deficits. This report highlights the importance to characterize additional patients with 7q11.23 atypical deletions comparing neuropsychological and clinical features between these individuals to shed light on the pathogenic role of genes within and flanking the WBS region.

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Induced chromosome deletions cause hypersociability and other features of Williams–Beuren syndrome in mice

Cited by 97 publications

References 56 publications

Negative Autoregulation of GTF2IRD1 in Williams-Beuren Syndrome via a Novel DNA Binding Mechanism

Negative Autoregulation of GTF2IRD1 in Williams-Beuren Syndrome via a Novel DNA Binding Mechanism

LIMK1 Regulates Long-Term Memory and Synaptic Plasticity via the Transcriptional Factor CREB

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits

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