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Physiol. Genomics 29: 109-117, 2007. First published December 26, 2006; doi:10.1152/physiolgenomics.00226.2006
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Functional nonsynonymous single nucleotide polymorphisms from the TGF-ß protein interaction network

¹ Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada
² Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
³ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
⁴ Centre for System Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
⁵ Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario, Canada

Protein complexes mediated by protein-protein interactions are essential for many cellular functions. Transforming growth factor (TGF)-ß signaling involves a cascade of protein-protein interactions and malfunctioning of this pathway has been implicated in human diseases. Using an in silico approach, we analyzed the naturally occurring human genetic variations from the proteins involved in the TGF-ß signaling (10 TGF-ß proteins and 242 other proteins interacting with them) to identify the ones that have potential biological consequences. All proteins were searched in the dbSNP database for the presence of nonsynonymous single nucleotide polymorphisms (nsSNPs). A total of 118 validated nsSNPs from 63 proteins were retrieved and analyzed in terms of 1) evolutionary conservation status, 2) being located in a functional protein domain or motif, and 3) altering putative protein motif or phosphorylation sites. Our results indicated the presence of 31 nsSNPs that occurred at evolutionarily conserved residues, 37 nsSNPs were located in protein domains, motifs, or repeats, and 46 nsSNPs were predicted to either create or abolish putative protein motifs or phosphorylation sites. We undertook this study to analyze the human genetic variations that can affect the protein function and the TGF-ß signaling. The nsSNPs reported in here can be characterized by experimental approaches to elucidate their exact biological roles and whether they are related to human disease.

transforming growth factor-ß pathway; protein-protein interactions; evolutionary conservation analysis; protein domains and motifs; phosphorylation sites