The Cross-Border Biotech Blog

Biotechnology, Health and Business in Canada, the United States and Worldwide

Friday Science Review: April 6, 2012

Mutations in the CFTR gene, which encodes a chloride channel expressed on the apical membranes of surface epithelial cells, can lead to dysregulation of ion conduction and solute trafficking in these cells. This dysregulation manifests as the accumulation of thicker than normal mucus in the lungs, digestive tract and other areas and it is the inability to clear this mucus that leads to the health consequences for cystic fibrosis (CF) patients.

Over 1900 different mutations and sequence variations in the CFTR gene have been identified and this increase in understanding will allow the development of treatments that target the underlying molecular defect, as demonstrated by the recent approval of Vertex Pharmaceuticals’ Kalydeco, a CFTR potentiator, which increases chloride flux through CFTR channels containing the G551D mutation found in ~4% of CF patients.

However, even in individuals that share the same molecular change to the CFTR gene, there are substantial variations in the disease severity and in the organs affected. The disease pathophysiology is therefore being modulated by variations in other genes. Researchers at the Biostatistics division of the Dalla Lana School of Health and the Department of Statistics of the University of Toronto sought to identify the variations that are associated with meconium ilius (MI), a severe intestinal obstruction at birth that is highly indicative of CF, by carrying out genome wide association studies. Using SNP’s from thousands of CF sufferers born with MI they found associations with variations in three genes that encode members of the solute carrier family of secondary transporter proteins (SLC6A14, SLC26A9, and SLC9A3) and association of MI with multiple other genes that are constituents of the apical plasma membrane.

Identification of these genes helps further develop understanding of the molecular mechanism of the disease i.e. how is the system level function perturbed by the altered chloride levels, as well as opening up new avenues for treating CF by pharmacological modulation of the epithelium as a whole.

Other publications:

  • Differences in the Mechanisms of Proapoptotic BH3 Proteins Binding to Bcl-XL and Bcl-2 Quantified in Live MCF-7 Cells. Molecular Cell. McMaster University
  • PARP1 Parylation Promotes Silent Locus Transmission in the Nucleolus: The Suspicion Confirmed. Molecular Cell. Centre de recherche du CHUQ-Pavillon CHUL
  • Seventeen-gene signature from enriched Her2/Neu mammary tumor-initiating cells predicts clinical outcome for human HER2+:ERα- breast cancer. PNAS. Toronto General Research Institute

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