Novel loss‐of‐function mutation in MCM8 causes premature ovarian insufficiency
Abstract Background Premature ovarian insufficiency (POI) is one major cause of female infertility, minichromosome maintenance complex component 8 (MCM8) has been reported to be responsible for POI. Methods Whole‐exome sequencing was performed to identify the genetic variants of women with POI. Sang...
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| Format: | Article |
| Language: | English |
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Wiley
2020-04-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.1165 |
| _version_ | 1797301044781252608 |
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| author | Ya‐Xin Zhang Wen‐Bin He Wen‐Juan Xiao Lan‐Lan Meng Chen Tan Juan Du Guang‐Xiu Lu Ge Lin Yue‐Qiu Tan |
| author_facet | Ya‐Xin Zhang Wen‐Bin He Wen‐Juan Xiao Lan‐Lan Meng Chen Tan Juan Du Guang‐Xiu Lu Ge Lin Yue‐Qiu Tan |
| author_sort | Ya‐Xin Zhang |
| collection | DOAJ |
| description | Abstract Background Premature ovarian insufficiency (POI) is one major cause of female infertility, minichromosome maintenance complex component 8 (MCM8) has been reported to be responsible for POI. Methods Whole‐exome sequencing was performed to identify the genetic variants of women with POI. Sanger sequencing was used to validate the variants in all the family members. Various bioinformatic software was used for the pathogenicity assessment. Reverse transcription polymerase chain reaction (RT‐PCR), real‐time quantitative PCR, and a chromosomal instability study induced by mitomycin C were performed to analyze the functional effects of the variant. Results A novel homozygous frameshift mutation (NM_032485.4:c.351_354delAAAG) of MCM8 gene was identified in the patients, segregated with POI in this family. This mutation is predicted to produce truncated MCM8 protein and to be pathogenic. Reverse transcription polymerase chain reaction revealed that the frameshift mutation led to a remarkably reduced level of MCM8 transcript products, and chromosomal instability study showed that the ability of mutant MCM8 to repair DNA breaks was impaired. Conclusion We identified a novel homozygous frameshift mutation in the MCM8 gene in two affected sisters with POI, and functional analysis revealed that this mutation is pathogenic. Our findings enrich the MCM8 mutation spectrum and might help clinicians to make a precise diagnosis, thereby allowing better family planning and genetic counseling. |
| first_indexed | 2024-03-07T23:16:43Z |
| format | Article |
| id | doaj.art-2f4d6a6515e24df7a6b5a738ab90684e |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-03-07T23:16:43Z |
| publishDate | 2020-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-2f4d6a6515e24df7a6b5a738ab90684e2024-02-21T10:29:43ZengWileyMolecular Genetics & Genomic Medicine2324-92692020-04-0184n/an/a10.1002/mgg3.1165Novel loss‐of‐function mutation in MCM8 causes premature ovarian insufficiencyYa‐Xin Zhang0Wen‐Bin He1Wen‐Juan Xiao2Lan‐Lan Meng3Chen Tan4Juan Du5Guang‐Xiu Lu6Ge Lin7Yue‐Qiu Tan8Institute of Reproduction and Stem Cell Engineering School of Basic Medical Science Central South University Changsha Hunan PR ChinaInstitute of Reproduction and Stem Cell Engineering School of Basic Medical Science Central South University Changsha Hunan PR ChinaInstitute of Reproduction and Stem Cell Engineering School of Basic Medical Science Central South University Changsha Hunan PR ChinaReproductive and Genetic Hospital of CITIC‐Xiangya Changsha Hunan PR ChinaInstitute of Reproduction and Stem Cell Engineering School of Basic Medical Science Central South University Changsha Hunan PR ChinaInstitute of Reproduction and Stem Cell Engineering School of Basic Medical Science Central South University Changsha Hunan PR ChinaInstitute of Reproduction and Stem Cell Engineering School of Basic Medical Science Central South University Changsha Hunan PR ChinaInstitute of Reproduction and Stem Cell Engineering School of Basic Medical Science Central South University Changsha Hunan PR ChinaInstitute of Reproduction and Stem Cell Engineering School of Basic Medical Science Central South University Changsha Hunan PR ChinaAbstract Background Premature ovarian insufficiency (POI) is one major cause of female infertility, minichromosome maintenance complex component 8 (MCM8) has been reported to be responsible for POI. Methods Whole‐exome sequencing was performed to identify the genetic variants of women with POI. Sanger sequencing was used to validate the variants in all the family members. Various bioinformatic software was used for the pathogenicity assessment. Reverse transcription polymerase chain reaction (RT‐PCR), real‐time quantitative PCR, and a chromosomal instability study induced by mitomycin C were performed to analyze the functional effects of the variant. Results A novel homozygous frameshift mutation (NM_032485.4:c.351_354delAAAG) of MCM8 gene was identified in the patients, segregated with POI in this family. This mutation is predicted to produce truncated MCM8 protein and to be pathogenic. Reverse transcription polymerase chain reaction revealed that the frameshift mutation led to a remarkably reduced level of MCM8 transcript products, and chromosomal instability study showed that the ability of mutant MCM8 to repair DNA breaks was impaired. Conclusion We identified a novel homozygous frameshift mutation in the MCM8 gene in two affected sisters with POI, and functional analysis revealed that this mutation is pathogenic. Our findings enrich the MCM8 mutation spectrum and might help clinicians to make a precise diagnosis, thereby allowing better family planning and genetic counseling.https://doi.org/10.1002/mgg3.1165loss‐of‐functionMCM8 genepremature ovarian insufficiencywhole‐exome sequencing |
| spellingShingle | Ya‐Xin Zhang Wen‐Bin He Wen‐Juan Xiao Lan‐Lan Meng Chen Tan Juan Du Guang‐Xiu Lu Ge Lin Yue‐Qiu Tan Novel loss‐of‐function mutation in MCM8 causes premature ovarian insufficiency Molecular Genetics & Genomic Medicine loss‐of‐function MCM8 gene premature ovarian insufficiency whole‐exome sequencing |
| title | Novel loss‐of‐function mutation in MCM8 causes premature ovarian insufficiency |
| title_full | Novel loss‐of‐function mutation in MCM8 causes premature ovarian insufficiency |
| title_fullStr | Novel loss‐of‐function mutation in MCM8 causes premature ovarian insufficiency |
| title_full_unstemmed | Novel loss‐of‐function mutation in MCM8 causes premature ovarian insufficiency |
| title_short | Novel loss‐of‐function mutation in MCM8 causes premature ovarian insufficiency |
| title_sort | novel loss of function mutation in mcm8 causes premature ovarian insufficiency |
| topic | loss‐of‐function MCM8 gene premature ovarian insufficiency whole‐exome sequencing |
| url | https://doi.org/10.1002/mgg3.1165 |
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