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

被引:0
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作者
Kajal Biswas
Martin Couillard
Luca Cavallone
Sandra Burkett
Stacey Stauffer
Betty K. Martin
Eileen Southon
Susan Reid
Teri M. Plona
Ryan N. Baugher
Stephanie D. Mellott
Kristen M. Pike
Mary E. Albaugh
Chelsea Maedler-Kron
Nancy Hamel
Lino Tessarollo
Victoria Marcus
William D. Foulkes
Shyam K. Sharan
机构
[1] National Institutes of Health,Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute
[2] McGill University,The Lady Davis Institute of the Jewish General Hospital
[3] Inc. Frederick National Laboratory for Cancer Research,Leidos Biomedical Research
[4] Inc. Frederick National Laboratory for Cancer Research,CLIA Molecular Diagnostics Laboratory, Leidos Biomedical Research
[5] McGill University,Department of Pathology
[6] McGill University,Department of Oncology
[7] McGill University,Department of Human Genetics
[8] McGill University,Department of Medical Genetics, Jewish General Hospital
[9] McGill University,Department of Medical Genetics and Cancer Research Program, Research Institute of the McGill University Health Centre
来源
Cell Death & Disease | / 12卷
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摘要
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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