Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment.

Autor: Bhattacharjee R; Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia.; Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia., Jolly LA; Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia.; School of Biomedicine, The University of Adelaide, Adelaide, SA, 5005, Australia., Corbett MA; Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia.; Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia., Wee IC; Discipline of Anatomy and Pathology, School of Biomedicine, The University of Adelaide, Adelaide, SA, 5005, Australia., Rao SR; Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia.; Proteomics, Metabolomics and MS-imaging Core Facility, South Australian Health and Medical Research Institute, and Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia., Gardner AE; Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia.; Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia., Ritchie T; Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia.; Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia., van Hugte EJH; Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behavior, Nijmegen, 6500, HB, the Netherlands., Ciptasari U; Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behavior, Nijmegen, 6500, HB, the Netherlands., Piltz S; Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia.; School of Biomedicine, The University of Adelaide, Adelaide, SA, 5005, Australia.; South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia., Noll JE; School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide and Precision Cancer Medicine Theme, Solid Tumour Program, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia., Nazri N; Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia.; Childhood Dementia Research Group, College of Medicine and Public Health, Flinders Health & Medical Research Institute, Flinders University, Bedford Park, Adelaide, SA, 5042, Australia., van Eyk CL; Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia.; Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia., White M; Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia.; School of Biomedicine, The University of Adelaide, Adelaide, SA, 5005, Australia.; South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia., Fornarino D; Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia.; Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia., Poulton C; Undiagnosed Diseases Program, Genetic Services of WA, King Edward Memorial Hospital, Subiaco, WA, 6008, Australia., Baynam G; Undiagnosed Diseases Program, Genetic Services of WA, King Edward Memorial Hospital, Subiaco, WA, 6008, Australia.; Western Australian Register of Developmental Anomalies, King Edward Memorial Hospital, Subiaco, WA, 6008, Australia.; Rare Care Centre, Perth Children's Hospital, Nedlands, WA, 6009, Australia., Collins-Praino LE; Discipline of Anatomy and Pathology, School of Biomedicine, The University of Adelaide, Adelaide, SA, 5005, Australia., Snel MF; Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia.; Proteomics, Metabolomics and MS-imaging Core Facility, South Australian Health and Medical Research Institute, and Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia., Nadif Kasri N; Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behavior, Nijmegen, 6500, HB, the Netherlands., Hemsley KM; Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia.; Childhood Dementia Research Group, College of Medicine and Public Health, Flinders Health & Medical Research Institute, Flinders University, Bedford Park, Adelaide, SA, 5042, Australia., Thomas PQ; Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia.; School of Biomedicine, The University of Adelaide, Adelaide, SA, 5005, Australia.; South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia., Kumar R; Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia.; Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia., Gecz J; Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia. jozef.gecz@adelaide.edu.au.; Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia. jozef.gecz@adelaide.edu.au.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Feb 08; Vol. 15 (1), pp. 1210. Date of Electronic Publication: 2024 Feb 08.
DOI: 10.1038/s41467-024-45121-5
Abstrakt: We implicated the X-chromosome THOC2 gene, which encodes the largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically complex neurodevelopmental disorder with intellectual disability as the core phenotype. To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic Thoc2 exon 37-38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37-38 deletion male (Thoc2 Δ/Y ) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2 Δ/Y mouse brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Overall, we suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and the patient, and DNA damage-associated functional alterations are at the root of THOC2 syndrome.
(© 2024. The Author(s).)
Databáze: MEDLINE
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