Exon deletion in the MSLN gene encoding MPF/mesothelin precursor protein during Laurasiatherian mammal evolution

Mesothelin is a cell surface glycoprotein that is present in normal mesothelial cells and is highly expressed in several human cancers, including mesotheliomas and ovarian, pancreatic, and lung cancers. The human mesothelin gene (MSLN) encodes a precursor protein, which is processed into 2 mature polypeptides: the N-terminal soluble megakaryocyte-potentiating factor (MPF) and the C-terminal membrane-bound mesothelin which functions as a cell adhesion molecule. In this study, we report the identification and sequence comparison of the MSLN genes in various mammalian species. We found that multiple exon deletion occurred in the Laurasiatherian MSLN genes including 6 exons in the cow, pig, horse, cat, dog, and panda genes and 8 exons in the hedgehog gene. The genomic deletion did not change the open reading frame of the resulting Laurasiatherian MSLN genes, producing internally deleted precursor proteins. The modified precursor was still able to produce the intact cell surface mesothelin protein but would not confer the MPF activity. Genomic sequence comparison showed that a breakage and rejoining event of ancestral introns 2 and 8 was responsible for the deletion. The present findings support that exon deletion is one of the molecular mechanisms underlying gene evolution in mammalian genomes.