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》

TFII-I gene family during tooth development: candidate genes for tooth anomalies in Williams syndrome.

Williams syndrome is a rare congenital disorder involving the cardiovascular system, mental retardation, distinctive facial features, and tooth anomalies. It is caused by the heterozygous deletion of approximately 1.6 Mb encompassing 28 genes on human chromosome 7q11.23. It has been suggested that the genes responsible for craniofacial anomalies are located in the telomeric end region, which harbors three members of the TFII-I gene family (Tassabehji et al. [2005] Science 310:1184). To recognize potential candidate genes for the tooth anomalies in Williams syndrome, we carried out comparative in situ hybridization analysis of members of TFII-I gene family during murine odontogenesis. Gtf2i showed widespread expression in the developing head but was higher in the developing teeth than surrounding tissues throughout tooth development. At the bud stage, Gtf2ird1 and Gtf2ird2 were expressed in the epithelial buds. At the early bell stage, expression of Gtf2ird1 and Gtf2ird2 was observed in preameloblasts and preodontoblasts.

Ohazama A ，Sharpe PT 《DEVELOPMENTAL DYNAMICS》

Isolation and characterisation of GTF2IRD2, a novel fusion gene and member of the TFII-I family of transcription factors, deleted in Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a developmental disorder with characteristic physical, cognitive and behavioural traits caused by a microdeletion of approximately 1.5 Mb on chromosome 7q11.23. In total, 24 genes have been described within the deleted region to date. We have isolated and characterised a novel human gene, GTF2IRD2, mapping to the WBS critical region thought to harbour genes important for the cognitive aspects of the disorder. GTF2IRD2 is the third member of the novel TFII-I family of genes clustered on 7q11.23. The GTF2IRD2 protein contains two putative helix-loop-helix regions (I-repeats) and an unusual C-terminal CHARLIE8 transposon-like domain, thought to have arisen as a consequence of the random insertion of a transposable element generating a functional fusion gene. The retention of a number of conserved transposase-associated motifs within the protein suggests that the CHARLIE8-like region may still have some degree of transposase functionality that could influence the stability of the region in a mechanism similar to that proposed for Charcot-Marie-Tooth neuropathy type 1A. GTF2IRD2 is highly conserved in mammals and the mouse ortholgue (Gtf2ird2) has also been isolated and maps to the syntenic WBS region on mouse chromosome 5G. Deletion mapping studies using somatic cell hybrids show that some WBS patients are hemizygous for this gene, suggesting that it could play a role in the pathogenesis of the disorder.

Tipney HJ ，Hinsley TA ，Brass A ，Metcalfe K ，Donnai D ，Tassabehji M ... -  《EUROPEAN JOURNAL OF HUMAN GENETICS》

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 ... -  《-》

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 ... -  《-》