Deciphering TCOF1 mutations in Chinese Treacher Collins syndrome patients: insights into pathogenesis and transcriptional disruption.

Publisher: BioMed Central Country of Publication: England NLM ID: 101266602 Publication Model: Electronic Cited Medium: Internet ISSN: 1750-1172 (Electronic) Linking ISSN: 17501172 NLM ISO Abbreviation: Orphanet J Rare Dis Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2006-

Mandibulofacial Dysostosis*/genetics ; Mutation*/genetics ; Nuclear Proteins*/genetics ; Phosphoproteins*/genetics; Humans ; Male ; Female ; Asian People/genetics ; East Asian People

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.
Competing Interests: Declarations. Ethics approval and consent to participate: The project was reviewed and approved by the Ethics Committees of the Plastic Surgery Hospital of the Peking Union Medical College and School of Biological Science, Beijing Tongren Hospital of Capital Medical University and Medical Engineering, Beihang University. The written informed consents were obtained from the parents of the under-age proband and the patient involved in this project. All procedures conform to the principles outlined in the Declaration of Helsinki. Consent for publication: The patient and the patients' parents provided written informed consent for the publication of any associated data and accompanying images. Competing interests: The authors declare that they have no competing interests.
(© 2024. The Author(s).)

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81970898 the National Natural Science Foundation of China; 82171844 the National Natural Science Foundation of China; 81571924 the National Natural Science Foundation of China; 81701930 the National Natural Science Foundation of China; YS202041 the Special Research Fund for Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

Keywords: TCOF1; Frameshift; Intrinsically disordered protein; Pathogenic; Treacher Collins syndrome

0 (TCOF1 protein, human)
0 (Nuclear Proteins)
0 (Phosphoproteins)

Date Created: 20250207 Date Completed: 20250208 Latest Revision: 20250210

20250210

PMC11806786

10.1186/s13023-024-03508-z

39920764