Biallelic variants in YRDC cause a developmental disorder with progeroid features
2021-09-20 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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Biallelic variants in YRDC cause a developmental disorder with progeroid features
Schmidt, J.; Goergens, J.; Pochechueva, T.; Kotter, A.; Schwenzer, N.; Sitte, M. & Werner, G. et al. (2021)
Human Genetics, 140(12) pp. 1679-1693. DOI: https://doi.org/10.1007/s00439-021-02347-3
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Details
- Authors
- Schmidt, Julia; Goergens, Jonas; Pochechueva, Tatiana; Kotter, Annika; Schwenzer, Niko; Sitte, Maren; Werner, Gesa; Altmüller, Janine; Thiele, Holger; Nürnberg, Peter; Isensee, Jörg; Li, Yun; Müller, Christian; Leube, Barbara; Reinhardt, H. Christian; Hucho, Tim; Salinas, Gabriela; Helm, Mark; Jachimowicz, Ron D.; Wieczorek, Dagmar; Kohl, Tobias; Lehnart, Stephan E.; Yigit, Gökhan; Wollnik, Bernd
- Abstract
- Abstract The highly conserved YrdC domain-containing protein (YRDC) interacts with the well-described KEOPS complex, regulating specific tRNA modifications to ensure accurate protein synthesis. Previous studies have linked the KEOPS complex to a role in promoting telomere maintenance and controlling genome integrity. Here, we report on a newborn with a severe neonatal progeroid phenotype including generalized loss of subcutaneous fat, microcephaly, growth retardation, wrinkled skin, renal failure, and premature death at the age of 12 days. By trio whole-exome sequencing, we identified a novel homozygous missense mutation, c.662T > C, in YRDC affecting an evolutionary highly conserved amino acid (p.Ile221Thr). Functional characterization of patient-derived dermal fibroblasts revealed that this mutation impairs YRDC function and consequently results in reduced t6A modifications of tRNAs. Furthermore, we established and performed a novel and highly sensitive 3-D Q-FISH analysis based on single-telomere detection to investigate the impact of YRDC on telomere maintenance. This analysis revealed significant telomere shortening in YRDC-mutant cells. Moreover, single-cell RNA sequencing analysis of YRDC-mutant fibroblasts revealed significant transcriptome-wide changes in gene expression, specifically enriched for genes associated with processes involved in DNA repair. We next examined the DNA damage response of patient’s dermal fibroblasts and detected an increased susceptibility to genotoxic agents and a global DNA double-strand break repair defect. Thus, our data suggest that YRDC may affect the maintenance of genomic stability. Together, our findings indicate that biallelic variants in YRDC result in a developmental disorder with progeroid features and might be linked to increased genomic instability and telomere shortening.
- Issue Date
- 20-September-2021
- Journal
- Human Genetics
- Project
- EXC 2067: Multiscale Bioimaging
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz
SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion
SFB 1002 | S02: Hochauflösende Fluoreszenzmikroskopie und integrative Datenanalyse - Working Group
- RG Lehnart
RG Wollnik - ISSN
- 0340-6717
- eISSN
- 1432-1203
- Language
- English
- Sponsor
- Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659
Georg-August-Universität Göttingen (1018)