Helmholtz Gemeinschaft


Biallelic variants in YRDC cause a developmental disorder with progeroid features

PDF (Original Paper) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
[img] Other (Supplementary Information)

Item Type:Article
Title:Biallelic variants in YRDC cause a developmental disorder with progeroid features
Creators Name:Schmidt, J. and Goergens, J. and Pochechueva, T. and Kotter, A. and Schwenzer, N. and Sitte, M. and Werner, G. and Altmueller, J. and Thiele, H. and Nürnberg, P. and Isensee, J. and Li, Y. and Müller, C. and Leube, B. and Reinhardt, H.C. and Hucho, T. and Salinas, G. and Helm, M. and Jachimowicz, R.D. and Wieczorek, D. and Kohl, T. and Lehnart, S.E. and Yigit, G. and Wollnik, B.
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.
Keywords:Alleles, Consanguinity, DNA Damage, Developmental Disabilities, GTP-Binding Proteins, Human Genome, Genomic Instability, Homozygote, Newborn Infant, Mutation, Pedigree, Progeria, Transfer RNA, RNA-Binding Proteins, RNA Sequence Analysis, Telomere Shortening
Source:Human Genetics
Page Range:1679-1693
Date:December 2021
Official Publication:https://doi.org/10.1007/s00439-021-02347-3
PubMed:View item in PubMed

Repository Staff Only: item control page


Downloads per month over past year

Open Access
MDC Library