Disruption of a Transcriptional Regulatory Pathway Contributes to Phenotypes in Carriers of Ataxia Telangiectasia

  • Denis Smirnov
  • Vivian G. Cheung
Part of the Lecture Notes in Computer Science book series (LNCS, volume 4955)


Ataxia Telangiectasia, AT, is a recessive disorder caused by mutations in the ATM gene. Although it is a recessive disorder, population-based studies have shown that carriers of AT have increased risks of breast cancer and other diseases compared to non-carriers. The goal of this study is to characterize phenotypes in AT carriers. Since expression level of genes is a major determinant of cellular phenotypes, we studied gene expression in AT carriers and identified regulatory mechanisms that influence these expression phenotypes.

We found gene expression phenotypes that showed a recessive pattern, where AT carriers are similar to non-carriers but differ from AT patients. However, there are also expression phenotypes that showed a dominant pattern where AT carriers are similar to AT patients but differ from non-carriers. One of the dominant gene expression phenotypes is that of TNFSF4. We showed that ATM regulates TNFSF4 expression through a transcriptional regulatory pathway that includes transcription factors and miRNAs. In AT carriers and AT patients, this pathway is disrupted, resulting in higher expression of TNFSF4. In this presentation, I will describe this ATM-mediated pathway, and show that the disruption of this pathway leads to increased risk of breast cancer and cardiac death in AT carriers. The integration of molecular and computational analyses of gene and microRNA expression revealed the complex consequences of a human gene mutation.

About the keynote speaker. Vivian Cheung is an investigator of the Howard Hughes Medical Institute and an Associate Professor of Pediatrics and Genetics at the University of Pennsylvania. She received her bachelor degree from the University of California, Los Angeles, and her MD from Tufts University. She received clinical training in Pediatrics and Neurology at the University of California, Los Angeles and The Childrens Hospital of Philadelphia. Her research focuses on identifying the genetic determinants of human traits and developing tools that facilitate such studies. Her lab has contributed to understanding the genetic basis of variation in human gene expression and characterizing gene expression phenotypes in carriers of autosomal recessive diseases, such as ataxia telangiectasia. Her group is also studying the genetic basis of variation in the frequencies and locations of human meiotic recombination.


Breast Cancer Study Gene Expression Expression Phenotype Clinical Training microRNA Expression 
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Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • Denis Smirnov
    • 1
  • Vivian G. Cheung
    • 1
  1. 1.University of Pennsylvania, Philadelphia 

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