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Biallelic variants in YRDC cause a developmental disorder with progeroid features.

Abstract (Expand)

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.

Authors: J. Schmidt, J. Goergens, T. Pochechueva, A. Kotter, N. Schwenzer, M. Sitte, G. Werner, J. Altmuller, H. Thiele, P. Nurnberg, J. Isensee, Y. Li, C. Muller, B. Leube, H. C. Reinhardt, T. Hucho, G. Salinas, M. Helm, R. D. Jachimowicz, D. Wieczorek, T. Kohl, S. E. Lehnart, G. Yigit, B. Wollnik

Date Published: 22nd Sep 2021

Publication Type: Journal

Caveolin3 Stabilizes McT1-Mediated Lactate/Proton Transport in Cardiomyocytes.

Abstract

[Figure: see text].

Authors: J. Peper, D. Kownatzki-Danger, G. Weninger, F. Seibertz, J. R. D. Pronto, H. Sutanto, D. Pacheu-Grau, R. Hindmarsh, S. Brandenburg, T. Kohl, G. Hasenfuss, M. Gotthardt, E. A. Rog-Zielinska, B. Wollnik, P. Rehling, H. Urlaub, J. Wegener, J. Heijman, N. Voigt, L. Cyganek, C. Lenz, S. E. Lehnart

Date Published: 19th Mar 2021

Publication Type: Journal

Intronic CRISPR Repair in a Preclinical Model of Noonan Syndrome-Associated Cardiomyopathy.

Abstract (Expand)

BACKGROUND: Noonan syndrome (NS) is a multisystemic developmental disorder characterized by common, clinically variable symptoms, such as typical facial dysmorphisms, short stature, developmental delay, … intellectual disability as well as cardiac hypertrophy. The underlying mechanism is a gain-of-function of the RAS-mitogen-activated protein kinase signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking. METHODS: Here, we present a family with two siblings displaying an autosomal recessive form of NS with massive hypertrophic cardiomyopathy as clinically the most prevalent symptom caused by biallelic mutations within the leucine zipper-like transcription regulator 1 (LZTR1). We generated induced pluripotent stem cell-derived cardiomyocytes of the affected siblings and investigated the patient-specific cardiomyocytes on the molecular and functional level. RESULTS: Patients' induced pluripotent stem cell-derived cardiomyocytes recapitulated the hypertrophic phenotype and uncovered a so-far-not-described causal link between LZTR1 dysfunction, RAS-mitogen-activated protein kinase signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Calcium channel blockade and MEK inhibition could prevent some of the disease characteristics, providing a molecular underpinning for the clinical use of these drugs in patients with NS, but might not be a sustainable therapeutic option. In a proof-of-concept approach, we explored a clinically translatable intronic CRISPR (clustered regularly interspaced short palindromic repeats) repair and demonstrated a rescue of the hypertrophic phenotype. CONCLUSIONS: Our study revealed the human cardiac pathogenesis in patient-specific induced pluripotent stem cell-derived cardiomyocytes from NS patients carrying biallelic variants in LZTR1 and identified a unique disease-specific proteome signature. In addition, we identified the intronic CRISPR repair as a personalized and in our view clinically translatable therapeutic strategy to treat NS-associated hypertrophic cardiomyopathy.

Authors: U. Hanses, M. Kleinsorge, L. Roos, G. Yigit, Y. Li, B. Barbarics, I. El-Battrawy, H. Lan, M. Tiburcy, R. Hindmarsh, C. Lenz, G. Salinas, S. Diecke, C. Muller, I. Adham, J. Altmuller, P. Nurnberg, T. Paul, W. H. Zimmermann, G. Hasenfuss, B. Wollnik, L. Cyganek

Date Published: 15th Sep 2020

Publication Type: Journal

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