Genetic mutations in ribosomal biogenesis gene TCOF1 identified in human neural tube defects
Abstract Background Rare mutations in multiple genes have been associated with human neural tube defects (NTDs), but their causative roles in NTDs disease are poorly understood. Insufficiency of the ribosomal biogenesis gene treacle ribosome biogenesis factor 1(Tcof1) results in cranial NTDs and cra...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-05-01
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| Series: | Molecular Genetics & Genomic Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mgg3.2150 |
| _version_ | 1797828638310137856 |
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| author | Fang Wang Haiqin Cheng Qin Zhang Jin Guo |
| author_facet | Fang Wang Haiqin Cheng Qin Zhang Jin Guo |
| author_sort | Fang Wang |
| collection | DOAJ |
| description | Abstract Background Rare mutations in multiple genes have been associated with human neural tube defects (NTDs), but their causative roles in NTDs disease are poorly understood. Insufficiency of the ribosomal biogenesis gene treacle ribosome biogenesis factor 1(Tcof1) results in cranial NTDs and craniofacial malformations in mice. Here, we aimed to identify genetic association of TCOF1 with human NTDs. Methods High‐throughput sequencing targeted on TCOF1 was performed on samples from 355 human cases affected by NTDs and 225 controls from a Han Chinese population. Results Four novel missense variants were found in the NTD cohort. Cell‐based assays indicated that the p.(A491G) variant carried by an individual, who shows anencephaly and single‐nostril abnormality, attenuates production of total proteins, suggesting a loss‐of‐function mutation in ribosomal biogenesis. Importantly, this variant promotes nucleolar disruption and stabilizes p53 protein, highlighting an unbalancing effect on cell apoptosis. Conclusions This study explored the functional impact of a missense variant in TCOF1, implicating a set of novel causative biological factors involved in the pathogenicity of human NTDs, particularly whom combined with craniofacial abnormality. |
| first_indexed | 2024-04-09T13:07:33Z |
| format | Article |
| id | doaj.art-fbd4b286e8724545aa67d90dc273cb0a |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-04-09T13:07:33Z |
| publishDate | 2023-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-fbd4b286e8724545aa67d90dc273cb0a2023-05-12T14:52:44ZengWileyMolecular Genetics & Genomic Medicine2324-92692023-05-01115n/an/a10.1002/mgg3.2150Genetic mutations in ribosomal biogenesis gene TCOF1 identified in human neural tube defectsFang Wang0Haiqin Cheng1Qin Zhang2Jin Guo3Beijing Municipal Key Laboratory of Child Development and Nutriomics Capital Institute of Pediatrics Beijing ChinaBeijing Municipal Key Laboratory of Child Development and Nutriomics Capital Institute of Pediatrics Beijing ChinaBeijing Municipal Key Laboratory of Child Development and Nutriomics Capital Institute of Pediatrics Beijing ChinaBeijing Municipal Key Laboratory of Child Development and Nutriomics Capital Institute of Pediatrics Beijing ChinaAbstract Background Rare mutations in multiple genes have been associated with human neural tube defects (NTDs), but their causative roles in NTDs disease are poorly understood. Insufficiency of the ribosomal biogenesis gene treacle ribosome biogenesis factor 1(Tcof1) results in cranial NTDs and craniofacial malformations in mice. Here, we aimed to identify genetic association of TCOF1 with human NTDs. Methods High‐throughput sequencing targeted on TCOF1 was performed on samples from 355 human cases affected by NTDs and 225 controls from a Han Chinese population. Results Four novel missense variants were found in the NTD cohort. Cell‐based assays indicated that the p.(A491G) variant carried by an individual, who shows anencephaly and single‐nostril abnormality, attenuates production of total proteins, suggesting a loss‐of‐function mutation in ribosomal biogenesis. Importantly, this variant promotes nucleolar disruption and stabilizes p53 protein, highlighting an unbalancing effect on cell apoptosis. Conclusions This study explored the functional impact of a missense variant in TCOF1, implicating a set of novel causative biological factors involved in the pathogenicity of human NTDs, particularly whom combined with craniofacial abnormality.https://doi.org/10.1002/mgg3.2150apoptosismissense mutationneural tube defectsribosomal biogenesisTCOF1 |
| spellingShingle | Fang Wang Haiqin Cheng Qin Zhang Jin Guo Genetic mutations in ribosomal biogenesis gene TCOF1 identified in human neural tube defects Molecular Genetics & Genomic Medicine apoptosis missense mutation neural tube defects ribosomal biogenesis TCOF1 |
| title | Genetic mutations in ribosomal biogenesis gene TCOF1 identified in human neural tube defects |
| title_full | Genetic mutations in ribosomal biogenesis gene TCOF1 identified in human neural tube defects |
| title_fullStr | Genetic mutations in ribosomal biogenesis gene TCOF1 identified in human neural tube defects |
| title_full_unstemmed | Genetic mutations in ribosomal biogenesis gene TCOF1 identified in human neural tube defects |
| title_short | Genetic mutations in ribosomal biogenesis gene TCOF1 identified in human neural tube defects |
| title_sort | genetic mutations in ribosomal biogenesis gene tcof1 identified in human neural tube defects |
| topic | apoptosis missense mutation neural tube defects ribosomal biogenesis TCOF1 |
| url | https://doi.org/10.1002/mgg3.2150 |
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