Biallelic variants in YRDC cause a developmental disorder with progeroid features

Julia Schmidt,Yun Li,Maren Sitte,Gökhan Yiğit ,Tatiana Pochechueva,Tobias Kohl,Ron D Jachimowicz,Peter Nürnberg,Stephan E Lehnart,Jonas Goergens,Barbara Leube,Mark Helm,Gesa Werner,Dagmar Wieczorek,Annika Kötter ,Christian Müller,Gabriela Salinas,Jörg Isensee,Niko Schwenzer,Tim Hucho,Janine Altmüller,Holger Thiele,Hans Christian Reinhardt ,Bernd Wollnik

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.

Highlights

Segmental progeroid syndromes are rare congenital disorders characterized by signs and symptoms of premature or accelerated aging
Mutations in genes encoding subunits of the KEOPS complex lead to decreased t6A levels and cause Galloway–Mowat syndrome (GAMOS, OMIM#251300), a rare autosomal recessive condition characterized by the association of early onset nephrotic syndrome and microcephaly with central nervous system anomalies (Braun et al 2017)
We present a patient with a severe developmental disorder with progeroid features caused by a novel homozygous missense mutation in YrdC domain-containing protein (YRDC)

Summary

Introduction

Segmental progeroid syndromes are rare congenital disorders characterized by signs and symptoms of premature or accelerated aging. Typical features of progeroid syndromes include, e.g., lipodystrophy, growth retardation, hair loss, brittle bones, atherosclerosis, and hearing loss. Several of these progeroid disorders show overlapping phenotypes, which makes specific clinical diagnosis often challenging. Identified cellular pathways and molecular pathomechanisms underlying premature aging mainly affect DNA damage repair processes, nuclear membrane dynamics, chromatin structure or transcription and, thereby, have an impact on various aspects of cell viability (Gordon et al 2014; Carrero et al 2016). The molecular characteristics of progeroid syndromes seem to be similar to those of “physiological” aging. Studying conditions of premature aging will help to reveal unknown underlying causal mechanisms and to develop potentially new treatments for more frequent age-associated diseases (Lessel and Kubisch 2019)

Methods

Results

Conclusion