Tissue-specific TCF4 triplet repeat instability revealed by optical genome mapping.

Autor:	Zarouchlioti C; UCL Institute of Ophthalmology, London, UK., Efthymiou S; UCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK., Facchini S; UCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK., Dominik N; UCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK., Bhattacharyya N; UCL Institute of Ophthalmology, London, UK., Liu S; UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK., Costa MA; UCL Institute of Ophthalmology, London, UK., Szabo A; UCL Institute of Ophthalmology, London, UK., Sadan AN; UCL Institute of Ophthalmology, London, UK., Jun AS; Cornea, Cataract, and External Disease Division, Wilmer Eye Institute, Johns Hopkins Medicine, Baltimore, USA., Bugiardini E; UCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK., Houlden H; UCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK., Cortese A; UCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK., Skalicka P; Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic., Dudakova L; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic., Muthusamy K; Moorfields Eye Hospital, London, UK., Cheetham ME; UCL Institute of Ophthalmology, London, UK., Hardcastle AJ; UCL Institute of Ophthalmology, London, UK., Liskova P; Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic., Tuft SJ; UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK., Davidson AE; UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK. Electronic address: alice.davidson@ucl.ac.uk.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2024 Oct; Vol. 108, pp. 105328. Date of Electronic Publication: 2024 Sep 14.
DOI:	10.1016/j.ebiom.2024.105328
Abstrakt:	Background: Fuchs endothelial corneal dystrophy (FECD) is the most common repeat-mediated disease in humans. It exclusively affects corneal endothelial cells (CECs), with ≤81% of cases associated with an intronic TCF4 triplet repeat (CTG18.1). Here, we utilise optical genome mapping (OGM) to investigate CTG18.1 tissue-specific instability to gain mechanistic insights. Methods: We applied OGM to a diverse range of genomic DNAs (gDNAs) from patients with FECD and controls (n = 43); CECs, leukocytes and fibroblasts. A bioinformatics pipeline was developed to robustly interrogate CTG18.1-spanning DNA molecules. All results were compared with conventional polymerase chain reaction-based fragment analysis. Findings: Analysis of bio-samples revealed that expanded CTG18.1 alleles behave dynamically, regardless of cell-type origin. However, clusters of CTG18.1 molecules, encompassing ∼1800-11,900 repeats, were exclusively detected in diseased CECs from expansion-positive cases. Additionally, both progenitor allele size and age were found to influence the level of leukocyte-specific CTG18.1 instability. Interpretation: OGM is a powerful tool for analysing somatic instability of repeat loci and reveals here the extreme levels of CTG18.1 instability occurring within diseased CECs underpinning FECD pathophysiology, opening up new therapeutic avenues for FECD. Furthermore, these findings highlight the broader translational utility of FECD as a model for developing therapeutic strategies for rarer diseases similarly attributed to somatically unstable repeats. Funding: UK Research and Innovation, Moorfields Eye Charity, Fight for Sight, Medical Research Council, NIHR BRC at Moorfields Eye Hospital and UCL Institute of Ophthalmology, Grantová Agentura České Republiky, Univerzita Karlova v Praze, the National Brain Appeal's Innovation Fund and Rosetrees Trust. Competing Interests: Declaration of interests The authors declare no competing interests. AED has previously acted as a paid consultant for Triplet Therapeutics Ltd, LoQus23 Therapeutics Ltd, Design Therapeutics Ltd and had a research collaboration with ProQR Therapeutics. AED has an ongoing research collaboration with Prime Medicine. (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu