Deciphering TCOF1 mutations in Chinese Treacher Collins syndrome patients: insights into pathogenesis and transcriptional disruption
Abstract Background Treacher Collins syndrome (TCS, MIM #154500), a severe congenital disorder, predominantly involves dysplasia of craniofacial bones and is characterized by features such as downslanting palpebral fissures, lower eyelid colobomas, microtia, and other craniofacial anomalies. Despite...
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BMC
2025-02-01
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| Series: | Orphanet Journal of Rare Diseases |
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| Online Access: | https://doi.org/10.1186/s13023-024-03508-z |
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| author | Zhuoyuan Jiang Ke Mao Bingqing Wang Hao Zhu Jiqiang Liu Ruirui Lang Baichuan Xiao Hailin Shan Qi Chen Ying Li Shouqin Zhao Qingguo Zhang Huisheng Liu Yong-Biao Zhang |
| author_facet | Zhuoyuan Jiang Ke Mao Bingqing Wang Hao Zhu Jiqiang Liu Ruirui Lang Baichuan Xiao Hailin Shan Qi Chen Ying Li Shouqin Zhao Qingguo Zhang Huisheng Liu Yong-Biao Zhang |
| author_sort | Zhuoyuan Jiang |
| collection | DOAJ |
| description | Abstract Background Treacher Collins syndrome (TCS, MIM #154500), a severe congenital disorder, predominantly involves dysplasia of craniofacial bones and is characterized by features such as downslanting palpebral fissures, lower eyelid colobomas, microtia, and other craniofacial anomalies. Despite its clinical importance, the underlying pathogenic mutations in TCS remain largely uncharacterized, representing a critical knowledge gap for researchers in the field. Results To address this, we performed mutation screening on a familial TCS case (trio) and 11 sporadic cases from a Chinese population. We identified 11 mutations predominantly localized to the central repeat domain (CRD) and the C-terminal domain (CTD, including the nuclear localization sequence) of TCOF1. The de novo frameshift mutation identified in the trio led to TCOF1 truncation, disrupting the central repeat domain crucial for binding transcriptional factors. Immunoprecipitation assays revealed that this pathogenic mutation attenuates the interaction between TCOF1 and transcription-related proteins, such as Pol II. Furthermore, cellular luciferase assays demonstrated that the mutation compromises the nuclear localization capability of TCOF1. Conclusions Our findings establish TCOF1 as the primary pathogenic gene in this Chinese TCS cohort, with mutations predominantly in the CRD and CTD, thereby expanding the known mutation spectrum of TCS and informing its prevention strategies. |
| format | Article |
| id | doaj-art-636e905c0fc44c9e88f0152e21e52a0d |
| institution | Kabale University |
| issn | 1750-1172 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj-art-636e905c0fc44c9e88f0152e21e52a0d2025-02-09T12:54:09ZengBMCOrphanet Journal of Rare Diseases1750-11722025-02-0120111210.1186/s13023-024-03508-zDeciphering TCOF1 mutations in Chinese Treacher Collins syndrome patients: insights into pathogenesis and transcriptional disruptionZhuoyuan Jiang0Ke Mao1Bingqing Wang2Hao Zhu3Jiqiang Liu4Ruirui Lang5Baichuan Xiao6Hailin Shan7Qi Chen8Ying Li9Shouqin Zhao10Qingguo Zhang11Huisheng Liu12Yong-Biao Zhang13School of Engineering Medicine, Beihang UniversitySchool of Engineering Medicine, Beihang UniversityDepartment of Ear Reconstruction, Plastic Surgery Hospital, Chinese Academy of Medical SciencesSchool of Engineering Medicine, Beihang UniversitySchool of Engineering Medicine, Beihang UniversitySchool of Engineering Medicine, Beihang UniversitySchool of Engineering Medicine, Beihang UniversitySchool of Engineering Medicine, Beihang UniversityDepartment of Ear Reconstruction, Plastic Surgery Hospital, Chinese Academy of Medical SciencesDepartment of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical UniversityDepartment of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical UniversityDepartment of Ear Reconstruction, Plastic Surgery Hospital, Chinese Academy of Medical SciencesBioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong LaboratorySchool of Engineering Medicine, Beihang UniversityAbstract Background Treacher Collins syndrome (TCS, MIM #154500), a severe congenital disorder, predominantly involves dysplasia of craniofacial bones and is characterized by features such as downslanting palpebral fissures, lower eyelid colobomas, microtia, and other craniofacial anomalies. Despite its clinical importance, the underlying pathogenic mutations in TCS remain largely uncharacterized, representing a critical knowledge gap for researchers in the field. Results To address this, we performed mutation screening on a familial TCS case (trio) and 11 sporadic cases from a Chinese population. We identified 11 mutations predominantly localized to the central repeat domain (CRD) and the C-terminal domain (CTD, including the nuclear localization sequence) of TCOF1. The de novo frameshift mutation identified in the trio led to TCOF1 truncation, disrupting the central repeat domain crucial for binding transcriptional factors. Immunoprecipitation assays revealed that this pathogenic mutation attenuates the interaction between TCOF1 and transcription-related proteins, such as Pol II. Furthermore, cellular luciferase assays demonstrated that the mutation compromises the nuclear localization capability of TCOF1. Conclusions Our findings establish TCOF1 as the primary pathogenic gene in this Chinese TCS cohort, with mutations predominantly in the CRD and CTD, thereby expanding the known mutation spectrum of TCS and informing its prevention strategies.https://doi.org/10.1186/s13023-024-03508-zTreacher Collins syndromeTCOF1FrameshiftPathogenicIntrinsically disordered protein |
| spellingShingle | Zhuoyuan Jiang Ke Mao Bingqing Wang Hao Zhu Jiqiang Liu Ruirui Lang Baichuan Xiao Hailin Shan Qi Chen Ying Li Shouqin Zhao Qingguo Zhang Huisheng Liu Yong-Biao Zhang Deciphering TCOF1 mutations in Chinese Treacher Collins syndrome patients: insights into pathogenesis and transcriptional disruption Orphanet Journal of Rare Diseases Treacher Collins syndrome TCOF1 Frameshift Pathogenic Intrinsically disordered protein |
| title | Deciphering TCOF1 mutations in Chinese Treacher Collins syndrome patients: insights into pathogenesis and transcriptional disruption |
| title_full | Deciphering TCOF1 mutations in Chinese Treacher Collins syndrome patients: insights into pathogenesis and transcriptional disruption |
| title_fullStr | Deciphering TCOF1 mutations in Chinese Treacher Collins syndrome patients: insights into pathogenesis and transcriptional disruption |
| title_full_unstemmed | Deciphering TCOF1 mutations in Chinese Treacher Collins syndrome patients: insights into pathogenesis and transcriptional disruption |
| title_short | Deciphering TCOF1 mutations in Chinese Treacher Collins syndrome patients: insights into pathogenesis and transcriptional disruption |
| title_sort | deciphering tcof1 mutations in chinese treacher collins syndrome patients insights into pathogenesis and transcriptional disruption |
| topic | Treacher Collins syndrome TCOF1 Frameshift Pathogenic Intrinsically disordered protein |
| url | https://doi.org/10.1186/s13023-024-03508-z |
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