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

Author:

Biswas Kajal,Couillard Martin,Cavallone Luca,Burkett SandraORCID,Stauffer Stacey,Martin Betty K.,Southon Eileen,Reid Susan,Plona Teri M.,Baugher Ryan N.,Mellott Stephanie D.,Pike Kristen M.ORCID,Albaugh Mary E.,Maedler-Kron Chelsea,Hamel Nancy,Tessarollo Lino,Marcus Victoria,Foulkes William D.ORCID,Sharan Shyam K.ORCID

Abstract

AbstractHereditary 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.

Funder

U.S. Department of Health & Human Services | National Institutes of Health

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology

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