Version 1
: Received: 10 April 2024 / Approved: 10 April 2024 / Online: 10 April 2024 (09:13:16 CEST)
How to cite:
Munteanu, C.V.; Marian, C.V.; Chirita-Emandi, A.; Puiu, M.; Trifa, A.P. In silico Splicing Analysis of the PMS2 Gene: Exploring Alternative Molecular Mechanisms in PMS2-Associated Lynch Syndrome. Preprints2024, 2024040719. https://doi.org/10.20944/preprints202404.0719.v1
Munteanu, C.V.; Marian, C.V.; Chirita-Emandi, A.; Puiu, M.; Trifa, A.P. In silico Splicing Analysis of the PMS2 Gene: Exploring Alternative Molecular Mechanisms in PMS2-Associated Lynch Syndrome. Preprints 2024, 2024040719. https://doi.org/10.20944/preprints202404.0719.v1
Munteanu, C.V.; Marian, C.V.; Chirita-Emandi, A.; Puiu, M.; Trifa, A.P. In silico Splicing Analysis of the PMS2 Gene: Exploring Alternative Molecular Mechanisms in PMS2-Associated Lynch Syndrome. Preprints2024, 2024040719. https://doi.org/10.20944/preprints202404.0719.v1
APA Style
Munteanu, C.V., Marian, C.V., Chirita-Emandi, A., Puiu, M., & Trifa, A.P. (2024). In silico Splicing Analysis of the PMS2 Gene: Exploring Alternative Molecular Mechanisms in PMS2-Associated Lynch Syndrome. Preprints. https://doi.org/10.20944/preprints202404.0719.v1
Chicago/Turabian Style
Munteanu, C.V., Maria Puiu and Adrian Pavel Trifa. 2024 "In silico Splicing Analysis of the PMS2 Gene: Exploring Alternative Molecular Mechanisms in PMS2-Associated Lynch Syndrome" Preprints. https://doi.org/10.20944/preprints202404.0719.v1
Abstract
Lynch syndrome (LS) is one of the most common hereditary cancer syndrome in human populations, associated with germline variants in MLH1, MSH2/EPCAM, MSH6 and PMS2 genes. The advent of next generation sequencing has proven a significant impact in germline variant detection in the causative genes; however, a large proportion of patients with clinical criteria still receive uncertain or negative results. PMS2 is the least frequent reported gene, associated with up to 15% of LS cases with late-onset disease and low penetrance phenotype; however, the proportion of PMS2-LS cases is considered to be highly underestimated. In this context, we consulted public available databases (ClinVar, LOVD) for missense and intronic PMS2 variants and performed an in silico analysis of the genomic sequence. Splicing bioinformatics tools proven effective in other genes were used to assess both the wild-type DNA sequence and reported genetic variants. Splicing alterations were predicted in silico and using GTEx short-read RNA expression data. Out of the 2384 missense variants discovered, 90% were classified with uncertain significance (VUS). 4.9% of missense variants were shown to have a potential splicing consequence (DS > 0.2) using SpliceAI. As described in the original publication, SpliceAI-visual was proven effective in annotation of short intronic variants (< 50 bp). Four short intronic variants were identified using SpliceAI-visual as potentially splicing disturbing, in spite of using a lower threshold (DS > 0.1). Moreover, we observed that Splicing Regulatory Elements (SREs) may play a fundamental role in alternative splicing in PMS2 gene, ESE motifs being overrepresented in highly expressed exons 5, 11 and 14. Computational analysis performed in our study serves as a valuable filtering step for guiding further RNA sequencing experiments. Additional functional data is necessary to evaluate the significance of our findings.
Keywords
Lynch syndrome; mismatch repair gene PMS2; alternative splicing; RNA splicing; splicing muta-tions; exon skipping; splicing regulatory elements
Subject
Medicine and Pharmacology, Oncology and Oncogenics
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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