Abstract
General transcription factor IIIC subunit 5 (GTF3C5) encodes transcription factor IIIC63 (TFIIIC63). It binds to DNA to recruit another transcription factor, TFIIIB, and RNA polymerase III (Pol III) to mediate the transcription of small noncoding RNAs, such as tRNAs. Here, we report four individuals from three families presenting with a multisystem developmental disorder phenotype with biallelic variants in GTF3C5. The overlapping features include growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, delayed bone age, skeletal anomalies, and facial dysmorphism. Using lymphoblastoid cell lines (LCLs) from two affected individuals, we observed a reduction in TFIIIC63 protein levels compared to control LCLs. Genome binding of TFIIIC63 protein is also reduced in LCL from one of the affected individuals. Additionally, approximately 40% of Pol III binding regions exhibited reduction in the level of Pol III occupancy in the mutant genome relative to the control, while approximately 54% of target regions showed comparable levels of Pol III occupancy between the two, indicating partial impairment of Pol III occupancy in the mutant genome. Yeasts with subject-specific variants showed temperature sensitivity and impaired growth, supporting the notion that the identified variants have deleterious effects. gtf3c5 mutant zebrafish showed developmental defects, including a smaller body, head, and eyes. Taken together, our data show that GTF3C5 plays an important role in embryonic development, and that biallelic variants in this gene cause a multisystem developmental disorder. Our study adds GTF3C5-related disorder to the growing list of genetic disorders associated with Pol III transcription machinery.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Acknowledgements
We are exceptionally grateful to the individuals and families who participated in this research study. We appreciate the GeneMatcher website (Sobreira et al. 2015) for facilitating the collaboration. We thank Jill Murrell Ph.D of Division of Genomic Diagnostics at Children’s Hospital of Philadelphia for assistance with variant submission to ClinVar.
Funding
KI was supported by the Children’s Hospital of Philadelphia Research Institute Institutional Developmental Fund, the Children’s Hospital of Philadelphia Junior Faculty Pilot Grant, the Children’s Hospital of Philadelphia Foerderer award, the Children’s Hospital of Philadelphia Pathology Support, and the Children’s Hospital of Philadelphia Roberts Collaborative. KS and KI were supported by Grant-in-Aid for Transformative Research Areas (A) 20H05940 (Japan Society for the Promotion of Science). KS was supported by Grant-in-Aid for Scientific Research (S) 20H05686 (Japan Society for the Promotion of Science) and CREST JPMJCR18S5 (Japan Science and Technology Agency). AI-O was partly supported by T32GM008638 and the Children’s Hospital of Philadelphia Roberts Collaborative. YK was supported by Japan Society for the Promotion of Science Overseas Research Fellowship.
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Aiko Iwata-Otsubo and Kosuke Izumi conceptualized and designed the study. Experiments and data analyses were performed by Aiko Iwata-Otsubo, Atsunori Yoshimura, Toyonori Sakata, Sarah K. Fiordaliso, Christoph Seiler, Katsuhiko Shirahige, and Kosuke Izumi. Data collection was performed by Cara M. Skraban, Cesar Augusto P Alves, Yukiko Kuroda, Jaime Vengoechea, Angela Grochowsky, Paige Ernste, Lauren Lulis, Addie Nesbitt, Ahmad Abou Tayoun, Christopher Gray, Meghan C Towne, Kelly Radtke, Elizabeth A Normand, Lindsay Rhodes, and Kosuke Izumi. The first draft of the manuscript was written by Aiko Iwata-Otsubo and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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MCT and KR are employees of Ambry Genetics. EAN and LR are employees of GeneDx, LLC.
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The following authors have no conflicts of interest to declare for this manuscript: AI-O,CMS, AY, TS, CAPA, SKF, YK, JV, AG, PE, LL, AN, AAT, CG, CS, KS, and KI. MCT and KR are employees of Ambry Genetics. EAN and LR are employees of GeneDx, LLC.
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Iwata-Otsubo, A., Skraban, C.M., Yoshimura, A. et al. Biallelic variants in GTF3C5, a regulator of RNA polymerase III-mediated transcription, cause a multisystem developmental disorder. Hum. Genet. 143, 437–453 (2024). https://doi.org/10.1007/s00439-024-02656-3
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DOI: https://doi.org/10.1007/s00439-024-02656-3