A Novel Splice-Site Mutation in MSH2 Is Associated With the Development of Lynch Syndrome
Lynch syndrome (LS) is an inherited autosomal dominant disorder caused by germline mutations of mismatch repair (MMR) genes, including MSH2, MSH6, PMS2, and MLH1. This study aimed to analyze the molecular defects and clinical manifestations of an affected family and propose appropriate individual pr...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-06-01
|
| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.00983/full |
| _version_ | 1811340763045298176 |
|---|---|
| author | Juyi Li Yuanyuan Li Haichun Ni Zhibin Yang Jian Chen Yarong Li Sheng Ding Xiaowan Jiang Mengjie Wang Li Li Xiaoyu Lv Xiaoyun Ruan Qian Jiang Zhang Lei Yong Cheng Juan Huang Aiping Deng |
| author_facet | Juyi Li Yuanyuan Li Haichun Ni Zhibin Yang Jian Chen Yarong Li Sheng Ding Xiaowan Jiang Mengjie Wang Li Li Xiaoyu Lv Xiaoyun Ruan Qian Jiang Zhang Lei Yong Cheng Juan Huang Aiping Deng |
| author_sort | Juyi Li |
| collection | DOAJ |
| description | Lynch syndrome (LS) is an inherited autosomal dominant disorder caused by germline mutations of mismatch repair (MMR) genes, including MSH2, MSH6, PMS2, and MLH1. This study aimed to analyze the molecular defects and clinical manifestations of an affected family and propose appropriate individual prevention strategies for all mutation carriers. A novel splicing mutation (c.1661+2 T>G) was identified in the MSH2 gene, which was found to co-segregate among affected family members by Whole exome sequencing (WES). RT-PCR analysis confirmed that c.1661+2 T>G could produce 3 transcripts, including 1 normal transcript and 2 aberrant transcripts. The 2 aberrant transcripts resulted in premature termination at the 6th nucleotide codon of MSH2 exon 11, so that the predicted products of the mutant MSH2 mRNAs were truncated proteins of 505 amino acids (with all of exon 10 deleted) and 528 amino acids (with a deletion of 82-nucleotides in exon 10), resulting in the loss of the interaction domain, the ATP domain and post-translationally modified residues. Quantitative RT-PCR (qRT-PCR) analysis showed that MSH2 mRNA levels in all patients were reduced to only 1/4 of the control levels. Our study reveals that a novel splicing mutation (c.1661+2 T>G) in the MSH2 gene causes LS and reaffirms the importance of genetic testing for LS. |
| first_indexed | 2024-04-13T18:46:44Z |
| format | Article |
| id | doaj.art-f1065cd2ed5c42f3b9c17f5a90ce85aa |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-13T18:46:44Z |
| publishDate | 2020-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-f1065cd2ed5c42f3b9c17f5a90ce85aa2022-12-22T02:34:34ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-06-011010.3389/fonc.2020.00983523012A Novel Splice-Site Mutation in MSH2 Is Associated With the Development of Lynch SyndromeJuyi Li0Yuanyuan Li1Haichun Ni2Zhibin Yang3Jian Chen4Yarong Li5Sheng Ding6Xiaowan Jiang7Mengjie Wang8Li Li9Xiaoyu Lv10Xiaoyun Ruan11Qian Jiang12Zhang Lei13Yong Cheng14Juan Huang15Aiping Deng16Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pathology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Information, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Information, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Oncology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Gastrointestinal Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Personnel, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaLynch syndrome (LS) is an inherited autosomal dominant disorder caused by germline mutations of mismatch repair (MMR) genes, including MSH2, MSH6, PMS2, and MLH1. This study aimed to analyze the molecular defects and clinical manifestations of an affected family and propose appropriate individual prevention strategies for all mutation carriers. A novel splicing mutation (c.1661+2 T>G) was identified in the MSH2 gene, which was found to co-segregate among affected family members by Whole exome sequencing (WES). RT-PCR analysis confirmed that c.1661+2 T>G could produce 3 transcripts, including 1 normal transcript and 2 aberrant transcripts. The 2 aberrant transcripts resulted in premature termination at the 6th nucleotide codon of MSH2 exon 11, so that the predicted products of the mutant MSH2 mRNAs were truncated proteins of 505 amino acids (with all of exon 10 deleted) and 528 amino acids (with a deletion of 82-nucleotides in exon 10), resulting in the loss of the interaction domain, the ATP domain and post-translationally modified residues. Quantitative RT-PCR (qRT-PCR) analysis showed that MSH2 mRNA levels in all patients were reduced to only 1/4 of the control levels. Our study reveals that a novel splicing mutation (c.1661+2 T>G) in the MSH2 gene causes LS and reaffirms the importance of genetic testing for LS.https://www.frontiersin.org/article/10.3389/fonc.2020.00983/fullLynch syndromehereditary non-polyposis colorectal cancerMSH2microsatellite instabilityaberrant splicinggenetic counseling |
| spellingShingle | Juyi Li Yuanyuan Li Haichun Ni Zhibin Yang Jian Chen Yarong Li Sheng Ding Xiaowan Jiang Mengjie Wang Li Li Xiaoyu Lv Xiaoyun Ruan Qian Jiang Zhang Lei Yong Cheng Juan Huang Aiping Deng A Novel Splice-Site Mutation in MSH2 Is Associated With the Development of Lynch Syndrome Frontiers in Oncology Lynch syndrome hereditary non-polyposis colorectal cancer MSH2 microsatellite instability aberrant splicing genetic counseling |
| title | A Novel Splice-Site Mutation in MSH2 Is Associated With the Development of Lynch Syndrome |
| title_full | A Novel Splice-Site Mutation in MSH2 Is Associated With the Development of Lynch Syndrome |
| title_fullStr | A Novel Splice-Site Mutation in MSH2 Is Associated With the Development of Lynch Syndrome |
| title_full_unstemmed | A Novel Splice-Site Mutation in MSH2 Is Associated With the Development of Lynch Syndrome |
| title_short | A Novel Splice-Site Mutation in MSH2 Is Associated With the Development of Lynch Syndrome |
| title_sort | novel splice site mutation in msh2 is associated with the development of lynch syndrome |
| topic | Lynch syndrome hereditary non-polyposis colorectal cancer MSH2 microsatellite instability aberrant splicing genetic counseling |
| url | https://www.frontiersin.org/article/10.3389/fonc.2020.00983/full |
| work_keys_str_mv | AT juyili anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT yuanyuanli anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT haichunni anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT zhibinyang anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT jianchen anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT yarongli anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT shengding anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT xiaowanjiang anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT mengjiewang anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT lili anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT xiaoyulv anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT xiaoyunruan anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT qianjiang anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT zhanglei anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT yongcheng anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT juanhuang anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT aipingdeng anovelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT juyili novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT yuanyuanli novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT haichunni novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT zhibinyang novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT jianchen novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT yarongli novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT shengding novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT xiaowanjiang novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT mengjiewang novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT lili novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT xiaoyulv novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT xiaoyunruan novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT qianjiang novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT zhanglei novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT yongcheng novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT juanhuang novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome AT aipingdeng novelsplicesitemutationinmsh2isassociatedwiththedevelopmentoflynchsyndrome |