Schmidt, Julia ORCID: 0000-0002-5942-2924, Goergens, Jonas, Pochechueva, Tatiana, Kotter, Annika, Schwenzer, Niko, Sitte, Maren, Werner, Gesa, Altmueller, Janine, Thiele, Holger, Nuernberg, Peter, Isensee, Joerg, Li, Yun, Mueller, Christian, Leube, Barbara, Reinhardt, H. Christian, Hucho, Tim ORCID: 0000-0002-4147-9308, Salinas, Gabriela, Helm, Mark, Jachimowicz, Ron D., Wieczorek, Dagmar, Kohl, Tobias, Lehnart, Stephan E., Yigit, Goekhan and Wollnik, Bernd ORCID: 0000-0003-2589-0364 (2021). Biallelic variants in YRDC cause a developmental disorder with progeroid features. Hum. Genet., 140 (12). S. 1679 - 1694. NEW YORK: SPRINGER. ISSN 1432-1203

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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 t(6)A 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schmidt, JuliaUNSPECIFIEDorcid.org/0000-0002-5942-2924UNSPECIFIED
Goergens, JonasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pochechueva, TatianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kotter, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwenzer, NikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sitte, MarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Werner, GesaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isensee, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, YunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leube, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hucho, TimUNSPECIFIEDorcid.org/0000-0002-4147-9308UNSPECIFIED
Salinas, GabrielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helm, MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jachimowicz, Ron D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wieczorek, DagmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kohl, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehnart, Stephan E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yigit, GoekhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDorcid.org/0000-0003-2589-0364UNSPECIFIED
URN: urn:nbn:de:hbz:38-602777
DOI: 10.1007/s00439-021-02347-3
Journal or Publication Title: Hum. Genet.
Volume: 140
Number: 12
Page Range: S. 1679 - 1694
Date: 2021
Publisher: SPRINGER
Place of Publication: NEW YORK
ISSN: 1432-1203
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
KEOPS-COMPLEX; SENESCENCE; TELOMERES; FAMILY; DAMAGE; SUA5PMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60277

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