GTF2IRD1 in Craniofacial Development of Humans and Mice

  title={GTF2IRD1 in Craniofacial Development of Humans and Mice},
  author={May Tassabehji and Peter Hammond and Annette Karmiloff-Smith and Pamela Thompson and Snorri Thorgeirsson and Marian E Durkin and Nicholas C. Popescu and Timothy J. Hutton and Kay A. Metcalfe and Agnes K Rucka and Helen Stewart and Andrew P. Read and Mark Maconochie and Dian Donnai},
  pages={1184 - 1187}
Craniofacial abnormalities account for about one-third of all human congenital defects, but our understanding of the genetic mechanisms governing craniofacial development is incomplete. We show that GTF2IRD1 is a genetic determinant of mammalian craniofacial and cognitive development, and we implicate another member of the TFII-I transcription factor family, GTF2I, in both aspects. Gtf2ird1-null mice exhibit phenotypic abnormalities reminiscent of the human microdeletion disorder Williams… 

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

It is shown 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.

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

It is shown 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.

Global Analysis of Gene Expression in the Developing Brain of Gtf2ird1 Knockout Mice

It is shown that differences in expression of genes on chromosome 5 were the result of retention of that chromosome region from the targeted embryonic stem cell line, and so were dependent upon strain rather than Gtf2ird1 genotype.

RNA-Seq analysis of Gtf2ird1 knockout epidermal tissue provides potential insights into molecular mechanisms underpinning Williams-Beuren syndrome

Gtf2ird1 inactivation results in widespread gene dysregulation, some of which may be due to the secondary consequences of gene regulatory network disruptions involving several transcription factors and signalling molecules.

Penetrance of craniofacial anomalies in mouse models of Smith-Magenis syndrome is modified by genomic sequence surrounding Rai1: not all null alleles are alike.

The complicated control of the penetrance for one phenotype in SMS mouse models provides tools to elucidate molecular mechanisms for penetrance and clearly shows that a null allele caused by chromosomal deletion can have different phenotypic consequences than one caused by gene inactivation.

Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder.

These mice recapitulate most crucial phenotypes of the human disorder, provide novel insights into the pathophysiological mechanisms of the disease such as the neural substrates of the behavioral manifestations, and will be valuable to evaluate novel therapeutic approaches.

Cdh1 regulates craniofacial development via APC-dependent ubiquitination and activation of Goosecoid

This study reveals a novel role for Cdh1 in craniofacial development through promoting APC-dependent non-proteolytic ubiquitination and activation of Gsc and reports that Gsc is also ubiquitinated and activated by the APCCdh1 E3 ubiquitin ligase, leading to transcriptional activation of various Gsc target genes crucial for cranioFacial development.

Haploinsufficiency of Gtf2i, a gene deleted in Williams Syndrome, leads to increases in social interactions

It is found that homozygous deletion of Gtf2i causes lethality during embryonic development with neural tube closure defects and exencephaly, consistent with other reports, and that GTF2I haploinsufficiency could be a contributor to the hypersociability in WBS patients.



Comparison of TFII‐I gene family members deleted in Williams‐Beuren syndrome

The identification of PEST, synergy control motifs, and sumoylation sites common to all family members suggest a shared mechanism regulating the stability and transcriptional activity of these factors.

Msx homeobox gene family and craniofacial development

This review summarizes studies on the expression, regulation, and functional analysis of Msx genes that bear relevance to craniofacial development in humans and mice.

Williams syndrome: use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes.

Genetic and psychometric testing of patients who have small deletions within the Williams syndrome critical region suggest that neither LIMK1 hemizygosity nor STX1A hemIZygosity is likely to contribute to any part of the WS phenotype, and they emphasize the importance of such patients for dissecting subtle but highly penetrant phenotypes.

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

A novel human gene is isolated and characterised, mapping to the WBS critical region thought to harbour genes important for the cognitive aspects of the disorder, and 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 transpos enzyme functionality that could influence the stability of the region.

Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice

Evidence is provided that mice with haploinsufficiency for Cyln2 have features reminiscent of Williams syndrome, including mild growth deficiency, brain abnormalities, hippocampal dysfunction and particular deficits in motor coordination, using a gene-targeting approach.

Mutational mechanisms of Williams-Beuren syndrome deletions.

This study determined the exact deletion size and LCR copy number in 74 patients with WBS, as well as precisely defined deletion breakpoints in 30 of them, using LCR-specific nucleotide differences, and proposed models for the specific pairing and precise aberrant recombination leading to each of the different germline rearrangements that occur in this region.

A transcription factor involved in skeletal muscle gene expression is deleted in patients with Williams syndrome

It is suggested that haploinsufficiency of the GTF3 gene may be the cause of abnormal muscle fatiguability in Williams-Beuren syndrome, and these genes may be members of a new family of transcription factors containing this HLH-like repeated motif.

Goosecoid is not an essential component of the mouse gastrula organizer but is required for craniofacial and rib development.

It is demonstrated that gsc is not essential for organizer activity in the mouse but is required later during embryogenesis for craniofacial and rib cage development and transplantation experiments suggest that the ovary does not provide gsc function to rescue gastrulation defects.

Williams syndrome: from genotype through to the cognitive phenotype.

Cognitive analysis of patients with small deletions in 7q11.23 which include elastin and LIM Kinase 1 have revealed varying results and it is premature to draw genotype-phenotype correlations.

Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome

Hemizygosity at the elastin locus is identified using genetic analyses in four familial and five sporadic cases of Williams syndrome, indicating that deletions involving oneElastin allele cause WS and implicate elast in hemizygosa in the pathogenesis of the disease.