Biallelic variants in YRDC cause a developmental disorder with progeroid features

Hum Genet. 2021 Dec;140(12):1679-1693. doi: 10.1007/s00439-021-02347-3.

Julia Schmidt ¹, Jonas Goergens ² ³, Tatiana Pochechueva ⁴, Annika Kotter ⁵, Niko Schwenzer ⁴ ⁶, Maren Sitte ⁷, Gesa Werner ⁸, Janine Altmüller ⁹ ¹⁰ ¹¹, Holger Thiele ⁹, Peter Nürnberg ⁹, Jörg Isensee ¹², Yun Li ⁸, Christian Müller ⁸, Barbara Leube ¹³, H Christian Reinhardt ¹⁴, Tim Hucho ¹², Gabriela Salinas ⁷, Mark Helm ⁵, Ron D Jachimowicz ² ³ ¹⁵ ¹⁶, Dagmar Wieczorek ¹³, Tobias Kohl ⁴ ¹⁷, Stephan E Lehnart ⁴ ¹⁷ ¹⁸ ⁶ ¹⁹ ²⁰, Gökhan Yigit ⁸, Bernd Wollnik ²¹ ²²

Affiliations

1 Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany. julia.schmidt1@med.uni-goettingen.de.
2 Max-Planck-Institute for Biology of Ageing, Cologne, Germany.
3 Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
4 Heart Research Center Göttingen, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.
5 Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-University Mainz, Mainz, Germany.
6 Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany.
7 NGS-Integrative Genomics Core Unit (NIG), Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
8 Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany.
9 Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
10 Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Facility Genomics, Charitéplatz 1, 10117, Berlin, Germany.
11 Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
12 Department of Anesthesiology and Intensive Care Medicine, Translational Pain Research, University Hospital of Cologne, Cologne, Germany.
13 Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
14 Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, German Cancer Consortium (DKTK Partner Site Essen), Essen, Germany.
15 Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
16 Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
17 DZHK (German Centre for Cardiovascular Research), partner site, Göttingen, Germany.
18 Collaborative Research Unit SFB 1002, University of Göttingen, Göttingen, Germany.
19 Collaborative Research Unit SFB 1190, University of Göttingen, Göttingen, Germany.
20 Transatlantic Network of Excellence CURE-PLaN, Fondation Leducq, Paris, France.
21 Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany. bernd.wollnik@med.uni-goettingen.de.
22 Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany. bernd.wollnik@med.uni-goettingen.de.

PMID: 34545459 DOI: 10.1007/s00439-021-02347-3

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.

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