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A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing

Hereditary non-polyposis colorectal cancer, now known as Lynch syndrome (LS) is one of the most common cancer predisposition syndromes and is caused by germline pathogenic variants (GPVs) in DNA mismatch repair (MMR) genes. A common founder GPV in PMS2 in the Canadian Inuit population, NM_000535.5:...

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Autores principales: Biswas, Kajal, Couillard, Martin, Cavallone, Luca, Burkett, Sandra, Stauffer, Stacey, Martin, Betty K., Southon, Eileen, Reid, Susan, Plona, Teri M., Baugher, Ryan N., Mellott, Stephanie D., Pike, Kristen M., Albaugh, Mary E., Maedler-Kron, Chelsea, Hamel, Nancy, Tessarollo, Lino, Marcus, Victoria, Foulkes, William D., Sharan, Shyam K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421400/
https://www.ncbi.nlm.nih.gov/pubmed/34489406
http://dx.doi.org/10.1038/s41419-021-04130-8
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author Biswas, Kajal
Couillard, Martin
Cavallone, Luca
Burkett, Sandra
Stauffer, Stacey
Martin, Betty K.
Southon, Eileen
Reid, Susan
Plona, Teri M.
Baugher, Ryan N.
Mellott, Stephanie D.
Pike, Kristen M.
Albaugh, Mary E.
Maedler-Kron, Chelsea
Hamel, Nancy
Tessarollo, Lino
Marcus, Victoria
Foulkes, William D.
Sharan, Shyam K.
author_facet Biswas, Kajal
Couillard, Martin
Cavallone, Luca
Burkett, Sandra
Stauffer, Stacey
Martin, Betty K.
Southon, Eileen
Reid, Susan
Plona, Teri M.
Baugher, Ryan N.
Mellott, Stephanie D.
Pike, Kristen M.
Albaugh, Mary E.
Maedler-Kron, Chelsea
Hamel, Nancy
Tessarollo, Lino
Marcus, Victoria
Foulkes, William D.
Sharan, Shyam K.
author_sort Biswas, Kajal
collection PubMed
description Hereditary non-polyposis colorectal cancer, now known as Lynch syndrome (LS) is one of the most common cancer predisposition syndromes and is caused by germline pathogenic variants (GPVs) in DNA mismatch repair (MMR) genes. A common founder GPV in PMS2 in the Canadian Inuit population, NM_000535.5: c.2002A>G, leads to a benign missense (p.I668V) but also acts as a de novo splice site that creates a 5 bp deletion resulting in a truncated protein (p.I668*). Individuals homozygous for this GPV are predisposed to atypical constitutional MMR deficiency with a delayed onset of first primary malignancy. We have generated mice with an equivalent germline mutation (Pms2c.1993A>G) and demonstrate that it results in a splicing defect similar to those observed in humans. Homozygous mutant mice are viable like the Pms2 null mice. However, unlike the Pms2 null mice, these mutant mice are fertile, like humans homozygous for this variant. Furthermore, these mice exhibit a significant increase in microsatellite instability and intestinal adenomas on an Apc mutant background. Rectification of the splicing defect in human and murine fibroblasts using antisense morpholinos suggests that this novel mouse model can be valuable in evaluating the efficacy aimed at targeting the splicing defect in PMS2 that is highly prevalent among the Canadian Inuits.
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spelling pubmed-84214002021-09-08 A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing Biswas, Kajal Couillard, Martin Cavallone, Luca Burkett, Sandra Stauffer, Stacey Martin, Betty K. Southon, Eileen Reid, Susan Plona, Teri M. Baugher, Ryan N. Mellott, Stephanie D. Pike, Kristen M. Albaugh, Mary E. Maedler-Kron, Chelsea Hamel, Nancy Tessarollo, Lino Marcus, Victoria Foulkes, William D. Sharan, Shyam K. Cell Death Dis Article Hereditary non-polyposis colorectal cancer, now known as Lynch syndrome (LS) is one of the most common cancer predisposition syndromes and is caused by germline pathogenic variants (GPVs) in DNA mismatch repair (MMR) genes. A common founder GPV in PMS2 in the Canadian Inuit population, NM_000535.5: c.2002A>G, leads to a benign missense (p.I668V) but also acts as a de novo splice site that creates a 5 bp deletion resulting in a truncated protein (p.I668*). Individuals homozygous for this GPV are predisposed to atypical constitutional MMR deficiency with a delayed onset of first primary malignancy. We have generated mice with an equivalent germline mutation (Pms2c.1993A>G) and demonstrate that it results in a splicing defect similar to those observed in humans. Homozygous mutant mice are viable like the Pms2 null mice. However, unlike the Pms2 null mice, these mutant mice are fertile, like humans homozygous for this variant. Furthermore, these mice exhibit a significant increase in microsatellite instability and intestinal adenomas on an Apc mutant background. Rectification of the splicing defect in human and murine fibroblasts using antisense morpholinos suggests that this novel mouse model can be valuable in evaluating the efficacy aimed at targeting the splicing defect in PMS2 that is highly prevalent among the Canadian Inuits. Nature Publishing Group UK 2021-09-06 /pmc/articles/PMC8421400/ /pubmed/34489406 http://dx.doi.org/10.1038/s41419-021-04130-8 Text en © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Biswas, Kajal
Couillard, Martin
Cavallone, Luca
Burkett, Sandra
Stauffer, Stacey
Martin, Betty K.
Southon, Eileen
Reid, Susan
Plona, Teri M.
Baugher, Ryan N.
Mellott, Stephanie D.
Pike, Kristen M.
Albaugh, Mary E.
Maedler-Kron, Chelsea
Hamel, Nancy
Tessarollo, Lino
Marcus, Victoria
Foulkes, William D.
Sharan, Shyam K.
A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing
title A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing
title_full A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing
title_fullStr A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing
title_full_unstemmed A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing
title_short A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing
title_sort novel mouse model of pms2 founder mutation that causes mismatch repair defect due to aberrant splicing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421400/
https://www.ncbi.nlm.nih.gov/pubmed/34489406
http://dx.doi.org/10.1038/s41419-021-04130-8
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