Two novel mutations in the MCM8 gene shared by two Chinese siblings with primary ovarian insufficiency and short stature
Abstract Background Minichromosome maintenance complex component 8 (MCM8) is responsible for homologous recombination and DNA double‐strand breaks (DSBs) repair and is the cause of primary ovarian insufficiency (POI), which is seldom diagnosed in adolescents and children. Methods Whole‐exome sequenc...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-09-01
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| Series: | Molecular Genetics & Genomic Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mgg3.1396 |
| _version_ | 1797301133756071936 |
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| author | Fei Wang Sheng Guo Pin Li |
| author_facet | Fei Wang Sheng Guo Pin Li |
| author_sort | Fei Wang |
| collection | DOAJ |
| description | Abstract Background Minichromosome maintenance complex component 8 (MCM8) is responsible for homologous recombination and DNA double‐strand breaks (DSBs) repair and is the cause of primary ovarian insufficiency (POI), which is seldom diagnosed in adolescents and children. Methods Whole‐exome sequencing was performed in a 13‐year‐old girl, and Sanger sequencing was used to identify potentially pathogenic variants in her sister (aged 6 years and 7 months) and parents. To identify potential pathogenic mutations, DSBs were induced by mitomycin C (MMC), and the DNA repair capacity was evaluated by the histone H2AX phosphorylation level. Results Two novel mutations of MCM8, i.e., c.724T>C (p.C242R) and c.1334C>A (p.S445*), were identified in a 13‐year‐old girl with POI who exhibited disappeared bilateral ovaries and short stature (height standard difference score [HtSDS] = −3.05), and her sister (aged 6 years and 7 months) with progressive POI whose ovary size decreased from normal to unclear and height growth gradually slowed. In the functional experiments, compared with the wild‐type, HeLa cells overexpressing mutant p.C242R and p.S445* showed a higher sensitivity to MMC. Furthermore, the mutant p.S445* has a more deleterious effect on DNA damage repair. Conclusion Our results reveal that affected children with the novel pathogenetic mutations p.C242R and p.S445* in the MCM8 gene are characterized by POI, short stature, cancer susceptibility, and genomic instability. |
| first_indexed | 2024-03-07T23:17:05Z |
| format | Article |
| id | doaj.art-8ac6c876e69a4a4b855e8b60d857634a |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-03-07T23:17:05Z |
| publishDate | 2020-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-8ac6c876e69a4a4b855e8b60d857634a2024-02-21T10:24:50ZengWileyMolecular Genetics & Genomic Medicine2324-92692020-09-0189n/an/a10.1002/mgg3.1396Two novel mutations in the MCM8 gene shared by two Chinese siblings with primary ovarian insufficiency and short statureFei Wang0Sheng Guo1Pin Li2Department of Endocrinology Shanghai Children’s HospitalShanghai Jiao Tong University Shanghai ChinaDepartment of Endocrinology Shanghai Children’s HospitalShanghai Jiao Tong University Shanghai ChinaDepartment of Endocrinology Shanghai Children’s HospitalShanghai Jiao Tong University Shanghai ChinaAbstract Background Minichromosome maintenance complex component 8 (MCM8) is responsible for homologous recombination and DNA double‐strand breaks (DSBs) repair and is the cause of primary ovarian insufficiency (POI), which is seldom diagnosed in adolescents and children. Methods Whole‐exome sequencing was performed in a 13‐year‐old girl, and Sanger sequencing was used to identify potentially pathogenic variants in her sister (aged 6 years and 7 months) and parents. To identify potential pathogenic mutations, DSBs were induced by mitomycin C (MMC), and the DNA repair capacity was evaluated by the histone H2AX phosphorylation level. Results Two novel mutations of MCM8, i.e., c.724T>C (p.C242R) and c.1334C>A (p.S445*), were identified in a 13‐year‐old girl with POI who exhibited disappeared bilateral ovaries and short stature (height standard difference score [HtSDS] = −3.05), and her sister (aged 6 years and 7 months) with progressive POI whose ovary size decreased from normal to unclear and height growth gradually slowed. In the functional experiments, compared with the wild‐type, HeLa cells overexpressing mutant p.C242R and p.S445* showed a higher sensitivity to MMC. Furthermore, the mutant p.S445* has a more deleterious effect on DNA damage repair. Conclusion Our results reveal that affected children with the novel pathogenetic mutations p.C242R and p.S445* in the MCM8 gene are characterized by POI, short stature, cancer susceptibility, and genomic instability.https://doi.org/10.1002/mgg3.1396adolescentsDNA repairMCM8primary ovarian insufficiencyshort stature |
| spellingShingle | Fei Wang Sheng Guo Pin Li Two novel mutations in the MCM8 gene shared by two Chinese siblings with primary ovarian insufficiency and short stature Molecular Genetics & Genomic Medicine adolescents DNA repair MCM8 primary ovarian insufficiency short stature |
| title | Two novel mutations in the MCM8 gene shared by two Chinese siblings with primary ovarian insufficiency and short stature |
| title_full | Two novel mutations in the MCM8 gene shared by two Chinese siblings with primary ovarian insufficiency and short stature |
| title_fullStr | Two novel mutations in the MCM8 gene shared by two Chinese siblings with primary ovarian insufficiency and short stature |
| title_full_unstemmed | Two novel mutations in the MCM8 gene shared by two Chinese siblings with primary ovarian insufficiency and short stature |
| title_short | Two novel mutations in the MCM8 gene shared by two Chinese siblings with primary ovarian insufficiency and short stature |
| title_sort | two novel mutations in the mcm8 gene shared by two chinese siblings with primary ovarian insufficiency and short stature |
| topic | adolescents DNA repair MCM8 primary ovarian insufficiency short stature |
| url | https://doi.org/10.1002/mgg3.1396 |
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