ArticleCell death & disease2021
A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing.
Article in Cell death & disease, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.
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Who cites it
9 citing papers in PubMed, 1 synthesis or guideline pooled it, 12 citations in OpenAlex.
- The role of DNA mismatch repair mutS/mutL homolog genes in spermatogenesis and male infertility: a systematic review and cohort study.Reproductive biology and endocrinology : RB&E · 2025Pooled it
- Advances in diagnostic and therapeutic applications of mismatch repair loss in cancer.DNA repair · 2025Review
- Postmenopausal osteoporosis increases periodontal inflammation and the pathogenicity of the oral microbiota in a rat model.Journal of oral microbiology · 2025Article
- In silico splicing analysis of the PMS2 gene: exploring alternative molecular mechanisms in PMS2-associated Lynch syndrome.BMC genomic data · 2024Article
- Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants.NPJ precision oncology · 2024Article
- Genetically engineered mouse models for hereditary cancer syndromes.Cancer science · 2023Review
- Review
- Genomic Microsatellite Signatures Identify Germline Mismatch Repair Deficiency and Risk of Cancer Onset.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2023Article
- Article
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Authors and funding
19 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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