title: Essential role of the N-terminal region of TFII-I in viability and behavior.
abstract: BACKGROUND
  GTF2I codes for a general intrinsic transcription factor and calcium channel regulator TFII-I, with high and ubiquitous expression, and a strong candidate for involvement in the morphological and neuro-developmental anomalies of the Williams-Beuren syndrome (WBS). WBS is a genetic disorder due to a recurring deletion of about 1,55-1,83 Mb containing 25-28 genes in chromosome band 7q11.23 including GTF2I. Completed homozygous loss of either the Gtf2i or Gtf2ird1 function in mice provided additional evidence for the involvement of both genes in the craniofacial and cognitive phenotype. Unfortunately nothing is now about the behavioral characterization of heterozygous mice.
  
  
  METHODS
  By gene targeting we have generated a mutant mice with a deletion of the first 140 amino-acids of TFII-I. mRNA and protein expression analysis were used to document the effect of the study deletion. We performed behavioral characterization of heterozygous mutant mice to document in vivo implications of TFII-I in the cognitive profile of WBS patients.
  
  
  RESULTS
  Homozygous and heterozygous mutant mice exhibit craniofacial alterations, most clearly represented in homozygous condition. Behavioral test demonstrate that heterozygous mutant mice exhibit some neurobehavioral alterations and hyperacusis or odynacusis that could be associated with specific features of WBS phenotype. Homozygous mutant mice present highly compromised embryonic viability and fertility. Regarding cellular model, we documented a retarded growth in heterozygous MEFs respect to homozygous or wild-type MEFs.
  
  
  CONCLUSIONS
  Our data confirm that, although additive effects of haploinsufficiency at several genes may contribute to the full craniofacial or neurocognitive features of WBS, correct expression of GTF2I is one of the main players. In addition, these findings show that the deletion of the fist 140 amino-acids of TFII-I altered it correct function leading to a clear phenotype, at both levels, at the cellular model and at the in vivo model.
authors.affiliation: Genetics Unit, de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Lucena
authors.forename: Susana
authors.initials: S
authors.lastname: Pezzi
authors.forename: Ester
authors.initials: E
authors.lastname: Aso
authors.forename: Maria C
authors.initials: MC
authors.lastname: Valero
authors.forename: Candelas
authors.initials: C
authors.lastname: Carreiro
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.forename: Adriana
authors.initials: A
authors.lastname: Sampaio
authors.forename: Maria
authors.initials: M
authors.lastname: Segura
authors.forename: Isabel
authors.initials: I
authors.lastname: Barthelemy
authors.forename: Marc Y
authors.initials: MY
authors.lastname: Zindel
authors.forename: Nuno
authors.initials: N
authors.lastname: Sousa
authors.forename: José L
authors.initials: JL
authors.lastname: Barbero
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.forename: Luis A
authors.initials: LA
authors.lastname: Pérez-Jurado
authors.forename: Victoria
authors.initials: V
authors.lastname: Campuzano
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D003072:Cognition Disorders / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D012001:Hyperacusis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D017384:Sequence Deletion; D019473:Transcription Factors, TFII / Q000235:genetics / Q000502:physiology*; D018980:Williams Syndrome / Q000235:genetics*
chemical_list: C486330:Gtf2i protein, mouse; D019473:Transcription Factors, TFII
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