Elsevier

Genomics

Volume 73, Issue 1, 1 April 2001, Pages 20-27
Genomics

Regular Article
Integration of a c-myc Transgene Results in Disruption of the Mouse Gtf2ird1 Gene, the Homologue of the Human GTF2IRD1 Gene Hemizygously Deleted in Williams–Beuren Syndrome

https://doi.org/10.1006/geno.2001.6507Get rights and content

Abstract

Transgenic mice expressing c-myc under the control of the albumin promoter and enhancer develop liver tumors and have served as a useful model for studying the progression of hepatocarcinogenesis. The chromosomes of one line of c-myc transgenic mice carry the reciprocal translocation t(5;6)(G1;F2) adjacent to the transgene insertion site on the 5G1–ter segment translocated to chromosome 6. To characterize the genomic alterations in the c-myc transgenic animals, we have cloned the mouse DNA flanking the transgene array. By linkage mapping, the transgene integration site was localized to the region of distal chromosome 5 syntenic to the region on human chromosome 7q11.23 that is hemizgygously deleted in Williams–Beuren syndrome, a multisystemic developmental disorder. Comparison of the genomic DNA structure in wildtype and transgenic mice revealed that the transgene integration had induced an ∼40-kb deletion, starting downstream of the Cyln2 gene and including the first exon of the Gtf2ird1 gene. Gtf2ird1 encodes a polypeptide related to general transcription factor TFII-I, and it is the mouse orthologue of GTF2IRD1 (WBSCR11), one of the genes commonly deleted in Williams–Beuren syndrome patients. Loss of the 5′ end of the Gtf2ird1 gene resulted in greatly reduced expression of Gtf2ird1 mRNA in mice homozygous for the transgene.

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    • Anxious, hypoactive phenotype combined with motor deficits in Gtf2ird1 null mouse model relevant to Williams syndrome

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      These discrepancies can be explained not only by differences in the background strains on which these models were created, but also by the method of transgenic engineering. Specifically: all four Gtf2ird1 models reported were created in a different manner and maintained on different background strains: Gtf2ird1Tg(Alb1-Myc)166.8Sst by insertion of a transgene on the mixed C57BL/CBAJ background [23,72]; Gtf2ird1tm1Lro by homologous recombination on a CD1 background[32,33]; and Gtf2ird1tm1Hrd by targeted insertion on a C57BL/6JArc background ([32,33]. A fourth model (Gtf2ird1Gt(XE465)Byg) with the most severe phenotype was generated by an insertion of a LacZ gene-trap cassette in Gtf2ird1on a C57BL/6 and 129Sv background, which in fact might have also disrupted GTF2I function, explaining the extremely severe phenotypes [30].

    • Negative autoregulation of GTF2IRD1 in Williams-Beuren syndrome via a novel DNA binding mechanism

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      Homozygous null mice from these lines do not have major developmental abnormalities, but show defects in brain function and behavioral alterations (22).5 The random insertion of a c-myc transgene led to the production of another Gtf2ird1 mutant mouse line (Tg(Alb1-Myc)166.8), due to a 40-kb deletion removing exon 1 and the Gtf2ird1 promoter (23). Homozygous null mice of this line have a mild craniofacial abnormality (24) and increased brain ventricle volume (25) but exhaustive behavioral testing was not done.

    • Recurrent and nonrandom DNA copy number and chromosome alterations in Myc transgenic mouse model for hepatocellular carcinogenesis: implications for human disease

      2009, Cancer Genetics and Cytogenetics
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      Therefore, the Myc transgenic mouse carrying the t(5;6) translocation, represents the first knockout of one of the genes present in the WBS critical region. GTF2IRD1 encodes a widely expressed, multifunctional helix–loop–helix transcription factor, which binds to pRb, although its role in carcinogenesis remains elusive [48]. In conclusion, the present results underscore the value of mouse models of HCC for identification of nonrandom and recurrent genomic alterations that are homologous to human and harbor a limited set of genes relevant to hepatocarcinogenesis.

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

      2007, Neurobiology of Disease
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      The orthologous region in the mouse lacks the characteristic duplicated blocks but has the full complement of genes, which is inverted with respect to the human map. The heterozygous GTF2IRD1 mutants (line 166.8) we used harbor a hypomorphic allele of GTF2IRD1 (Durkin et al., 2001), while the heterozygous CYLN2 mutants we used were derived from the null mutant of CLIP-115 (Hoogenraad et al., 2002). Both types of mutants mimic (part of) the genetic deletion in Williams Syndrome in that a suboptimal dosage of the respective gene is present.

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    Sequence data from this article have been deposited with the EMBL/GenBank Data Libraries under Accession Nos. AF257475–AF257477.

    1

    To whom correspondence should be addressed at Laboratory of Experimental Carcinogenesis, National Cancer Institute, Building 37, Room 3C28, 9000 Rockville Pike, Bethesda, MD 20892. Telephone:(301) 496-5688. Fax: (301) 496-0734. E-mail: [email protected].

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