Familiar colorectal cancer type X (FCCTX) comprises families that fulfill the Amsterdam criteria for hereditary non-polyposis colorectal cancer, but that lack the mismatch repair deficiency that defines the Lynch syndrome. Thus, the genetic cause that increases the predisposition to colorectal and other related cancers in families with FCCTX remains to be elucidated. Using whole-exome sequencing, we have identified a truncating mutation in the SETD6 gene (c.791_792insA, p.Met264IlefsTer3) in all the affected members of a FCCTX family. SETD6 is a mono-methyltransferase previously shown to modulate the NF-κB and Wnt signaling pathways, among other. In the present study, we characterized the truncated version of SETD6, providing evidence that this SETD6 mutation may play a role in the cancer inheritance in this family. Here we demonstrate that the truncated SETD6 lacks its enzymatic activity as a methyltransferase, while maintaining other properties such as its expression, localization and substrate-binding ability. In addition, we show that the mutant allele is expressed and that the resulting protein competes with the wild type for their substrates, pointing to a dominant negative nature. These findings suggest that the identified mutation impairs the normal function of SETD6, which may result in the deregulation of the different pathways in which it is involved, contributing to the increased susceptibility to cancer in this FCCTX family.
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