Gtf2i and Gtf2ird1 mutation do not account for the full phenotypic effect of the Williams syndrome critical region in mouse models.

Williams syndrome (WS) is a neurodevelopmental disorder caused by a 1.5-1.8 Mbp deletion on chromosome 7q11.23, affecting the copy number of 26-28 genes. Phenotypes of WS 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 WS 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 (CD) 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 CD 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 genes or combinations of genes beyond Gtf2i and Gtf2ird1 are necessary to produce these phenotypic effects.

Kopp N ，McCullough K ，Maloney SE ，Dougherty JD ... -  《-》

Functions of Gtf2i and Gtf2ird1 in the developing brain: transcription, DNA binding and long-term behavioral consequences.

Gtf2ird1 and Gtf2i are two transcription factors (TFs) among the 28 genes deleted in Williams syndrome, and prior mouse models of each TF show behavioral phenotypes. Here we identify their genomic binding sites in the developing brain and test for additive effects of their mutation on transcription and behavior. GTF2IRD1 binding targets were enriched for transcriptional and chromatin regulators and mediators of ubiquitination. GTF2I targets were enriched for signal transduction proteins, including regulators of phosphorylation and WNT. Both TFs are highly enriched at promoters, strongly overlap CTCF binding and topological associating domain boundaries and moderately overlap each other, suggesting epistatic effects. Shared TF targets are enriched for reactive oxygen species-responsive genes, synaptic proteins and transcription regulators such as chromatin modifiers, including a significant number of highly constrained genes and known ASD genes. We next used single and double mutants to test whether mutating both TFs will modify transcriptional and behavioral phenotypes of single Gtf2ird1 mutants, though with the caveat that our Gtf2ird1 mutants, like others previously reported, do produce low levels of a truncated protein product. Despite little difference in DNA binding and transcriptome-wide expression, homozygous Gtf2ird1 mutation caused balance, marble burying and conditioned fear phenotypes. However, mutating Gtf2i in addition to Gtf2ird1 did not further modify transcriptomic or most behavioral phenotypes, suggesting Gtf2ird1 mutation alone was sufficient for the observed phenotypes.

Kopp ND ，Nygaard KR ，Liu Y ，McCullough KB ，Maloney SE ，Gabel HW ，Dougherty JD ... -  《-》

Partial 7q11.23 deletions further implicate GTF2I and GTF2IRD1 as the main genes responsible for the Williams-Beuren syndrome neurocognitive profile.

Antonell A ，Del Campo M ，Magano LF ，Kaufmann L ，de la Iglesia JM ，Gallastegui F ，Flores R ，Schweigmann U ，Fauth C ，Kotzot D ，Pérez-Jurado LA ... -  《-》

Williams syndrome deficits in visual spatial processing linked to GTF2IRD1 and GTF2I on chromosome 7q11.23.

To identify the relationship between specific genes and phenotypic features of Williams syndrome. Subjects were selected based on their deletion status determined by fluorescence in situ hybridization using a panel of 24 BACs and cosmids spanning the region commonly deleted and single gene analysis using Southern blotting. From the cohort of subjects, three had atypical deletions. Physical examinations and cognitive tests were administered to the three subjects and the results were compared to those from a cohort of typical WS subjects. The molecular results indicate smaller deletions for each subject. In all three cases, typical Williams facies were absent and visual spatial abilities were above that of full deletion WS subjects, particularly in the qualitative aspects of visual spatial processing. Combining the molecular analysis with the cognitive results suggest that the genes GTF2IRD1 and GTF2I contribute to deficits on visual spatial functioning.

Hirota H ，Matsuoka R ，Chen XN ，Salandanan LS ，Lincoln A ，Rose FE ，Sunahara M ，Osawa M ，Bellugi U ，Korenberg JR ... -  《GENETICS IN MEDICINE》

Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome.

van Hagen JM ，van der Geest JN ，van der Giessen RS ，Lagers-van Haselen GC ，Eussen HJ ，Gille JJ ，Govaerts LC ，Wouters CH ，de Coo IF ，Hoogenraad CC ，Koekkoek SK ，Frens MA ，van Camp N ，van der Linden A ，Jansweijer MC ，Thorgeirsson SS ，De Zeeuw CI ... -  《NEUROBIOLOGY OF DISEASE》