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

Our plain-English summary of Exon deletion in the MSLN gene encoding MPF/mesothelin precursor protein during Laurasiatherian mammal evolution, by D.S. Kim, Y. Hahn (International Journal of Molecular Medicine, 2011).

The study

• Authors: D.S. Kim, Y. Hahn
• Journal: International Journal of Molecular Medicine
• Published: 2011;27(2):289-93
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

In plain English

This was a computer-based comparison of gene sequences. It did not study people, patients or asbestos exposure. The authors searched public genome databases for the MSLN gene. This gene makes a precursor protein that is split into two parts: megakaryocyte-potentiating factor (MPF), and mesothelin, a cell-surface protein found in normal mesothelial cells and in mesotheliomas. They compared the gene across mammals including humans, rhesus macaques, mice, rats, cows, pigs, horses, dogs, pandas and the European hedgehog. Human, mouse and rat genes had 16 coding exons (gene segments). The cow, pig, horse, dog and panda genes had only 10, lacking the six that correspond to human exons 3 to 8. The hedgehog gene lacked eight. The cow protein was 403 amino acids long, compared with 622 in humans. The authors predicted that the shortened proteins could still form cell-surface mesothelin but should lack MPF activity. They concluded that the loss occurred in a common ancestor of the mammal group Laurasiatheria, apparently through DNA breakage and rejoining, and that exon deletion is one mechanism of gene evolution in mammals.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Comparative genomics (computer analysis of published genome sequences); no laboratory, animal or human subjects study
• Who was studied: MSLN gene and protein sequences from public databases for humans, chimpanzees, rhesus macaques, mice, rats, cats, pandas, dogs, horses, pigs, cows and chickens (UCSC genome assemblies), plus whole genome shotgun contigs for the European hedgehog
• Exposure: No asbestos or other exposure was studied; the article compares the structure of the MSLN gene across species
• Main results:
  • Human, mouse and rat MSLN genes each had 16 coding exons, while the cow gene had only 10 coding exons, missing the 6 that correspond to human coding exons 3-8
  • The human, mouse and rat precursor proteins were 622, 625 and 625 amino acids long; the cow protein was 403 amino acids
  • Comparison with the related MSLNL gene indicated the 6 exons were part of the ancestral gene and were lost in the cow lineage, rather than added in the others
  • The cow, pig, horse, dog and panda MSLN genes all had only 10 coding exons
  • The hedgehog gene lacked 8 exons, corresponding to human coding exons 2-9, and its protein was missing the entire MPF region
  • In the cow, pig, horse, dog and panda proteins, the signal peptide cleavage site and the furin-like convertase target sequence were retained, indicating the precursor could still be split into two mature proteins
  • The deletion did not change the reading frame of the gene. The authors inferred the shortened proteins should have no megakaryocyte-potentiating activity but should keep the cell adhesion function of mesothelin
  • No sequence similarity was found between human introns 2 and 8, so the authors judged that homologous recombination was not involved. A breakage and rejoining of the ancestral introns 2 and 8 via non-homologous end joining (NHEJ) seemed responsible for the deletion
• The authors' conclusion: The authors concluded that the deletion of exons 3-8 occurred in a common ancestor of Laurasiatheria, with 2 more exons later lost in the hedgehog lineage, and that exon deletion is one of the mechanisms driving gene evolution in the mammalian genome

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Glycoprotein, Mesothelial Cells, Mesothelioma, Lung Cancer.

Related studies

• Mesothelin (MSLN) promoter is hypomethylated in malignant mesothelioma, but its expression is not associated with methylation status of the promoter — K. Tan, K. Kajino, et al. (2010)
• Polymorphisms in the putative micro-RNA-binding sites of mesothelin gene are associated with serum levels of mesothelin-related protein — A. Cristaudo, R. Foddis, et al. (2010)
• Comparison of osteopontin, megakaryocyte potentiating factor, and mesothelin proteins as markers in the serum of patients with malignant mesothelioma — J. Creaney, D. Yeoman, et al. (2008)
• Mesothelin (MSLN) methylation and soluble mesothelin-related protein levels in a Chinese asbestos-exposed population — M. Yu, Y. Zhang, et al. (2015)
• Comparison of the diagnostic accuracy of the MSLN gene products, mesothelin and megakaryocyte potentiating factor, as biomarkers for mesothelioma in pleural effusions and serum — J. Creaney, S. Sneddon, et al. (2013)
• Mesothelin-family proteins and diagnosis of mesothelioma — B.W. Robinson, J. Creaney, et al. (2003)

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