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Characterization of the porcine ATM gene: towards the generation of a novel non-murine animal model for Ataxia-Telangiectasia.

Publication ,  Journal Article
Rogatcheva, MB; Fritz, KL; Rund, LA; Pollock, CB; Beever, JE; Counter, CM; Schook, LB
Published in: Gene
December 15, 2007

Ataxia-Telangiectasia (A-T) is a genetic disorder causing cerebellar degeneration, immune deficiency, cancer predisposition, chromosomal instability and radiation sensitivity. Among the mutations responsible for A-T, 85% represent truncating mutations that result in the production of shorter, highly unstable forms of ATM (AT-mutated) protein leading to a null ATM phenotype. Several ATM-deficient mice have been created however none reflects the extent of neurological degeneration observed in humans. In an attempt to identify an alternative animal model, we have characterized the porcine ortholog of ATM (pATM). When compared to the human ATM (hATM), the pATM showed a high level of homology in the coding region, particularly in the regions coding for functional domains, and had extensive alternative splicing of the 5'UTR, characteristic for the human ATM mRNA. Six different 5'UTRs resulting from alternative splicing of the first three exons were identified. The porcine 5'UTRs varied in size, had multiple ATG codons and different secondary structures, supporting the possibility of complex transcriptional regulation. Three of the six transcripts demonstrated alternative splicing of exon 3, the first putative coding exon, altering the translation start and giving rise to a putative protein lacking the N-terminus substrate binding domain (82-89 aa) involved in activation of human p53 and BRCA1 pathways. Real time-PCR analysis revealed variable expression levels of total ATM transcripts in individual tissues. Although each splice variant was ubiquitously expressed among the tissues, differences in the relative abundances of specific 5'UTRs were observed. The extensive alternative splicing of the pATM gene resembles the complex splicing observed in the hATM and could provide insights for differences observed between mice and humans with regards to the onset of A-T. Thus, the pig may provide a more relevant clinical model of A-T.

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Published In

Gene

DOI

ISSN

0378-1119

Publication Date

December 15, 2007

Volume

405

Issue

1-2

Start / End Page

27 / 35

Location

Netherlands

Related Subject Headings

  • Tumor Suppressor Proteins
  • Swine
  • Sequence Homology, Nucleic Acid
  • Sequence Homology, Amino Acid
  • Reverse Transcriptase Polymerase Chain Reaction
  • Protein Serine-Threonine Kinases
  • Promoter Regions, Genetic
  • Mutation
  • Molecular Sequence Data
  • Humans
 

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Rogatcheva, M. B., Fritz, K. L., Rund, L. A., Pollock, C. B., Beever, J. E., Counter, C. M., & Schook, L. B. (2007). Characterization of the porcine ATM gene: towards the generation of a novel non-murine animal model for Ataxia-Telangiectasia. Gene, 405(1–2), 27–35. https://doi.org/10.1016/j.gene.2007.08.014
Rogatcheva, Margarita B., Krista L. Fritz, Laurie A. Rund, Callie B. Pollock, Jonathan E. Beever, Christopher M. Counter, and Lawrence B. Schook. “Characterization of the porcine ATM gene: towards the generation of a novel non-murine animal model for Ataxia-Telangiectasia.Gene 405, no. 1–2 (December 15, 2007): 27–35. https://doi.org/10.1016/j.gene.2007.08.014.
Rogatcheva MB, Fritz KL, Rund LA, Pollock CB, Beever JE, Counter CM, et al. Characterization of the porcine ATM gene: towards the generation of a novel non-murine animal model for Ataxia-Telangiectasia. Gene. 2007 Dec 15;405(1–2):27–35.
Rogatcheva, Margarita B., et al. “Characterization of the porcine ATM gene: towards the generation of a novel non-murine animal model for Ataxia-Telangiectasia.Gene, vol. 405, no. 1–2, Dec. 2007, pp. 27–35. Pubmed, doi:10.1016/j.gene.2007.08.014.
Rogatcheva MB, Fritz KL, Rund LA, Pollock CB, Beever JE, Counter CM, Schook LB. Characterization of the porcine ATM gene: towards the generation of a novel non-murine animal model for Ataxia-Telangiectasia. Gene. 2007 Dec 15;405(1–2):27–35.
Journal cover image

Published In

Gene

DOI

ISSN

0378-1119

Publication Date

December 15, 2007

Volume

405

Issue

1-2

Start / End Page

27 / 35

Location

Netherlands

Related Subject Headings

  • Tumor Suppressor Proteins
  • Swine
  • Sequence Homology, Nucleic Acid
  • Sequence Homology, Amino Acid
  • Reverse Transcriptase Polymerase Chain Reaction
  • Protein Serine-Threonine Kinases
  • Promoter Regions, Genetic
  • Mutation
  • Molecular Sequence Data
  • Humans