Clinical and genetic characterization of a progressive RBL2-associated neurodevelopmental disorder.

Autor:	Aughey GN; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK., Cali E; Department of Neuromuscular diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK., Maroofian R; Department of Neuromuscular diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK., Zaki MS; Department of Clinical Genetics, Human Genetics and Genome Research Institute, National Research Centre, Dokki, Cairo 12622, Egypt., Pagnamenta AT; NIHR Oxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, OX3 9DU, UK., Ali Z; Centre for Biotechnology and Microbiology, University of Swat, Charbagh, Swat, Khyber Pakhtunkhwa 19120, Pakistan., Abdulllah U; University Institute of Biochemistry and Biotechnology (UIBB), PMAS-Arid Agriculture University Rawalpindi, Rawalpindi 46300, Pakistan., Rahman F; Department of Developmental-Behavioral Pediatrics, The Children's Hospital, University of Child Health Sciences (UCHS-CH), Lahore 54600, Pakistan., Menzies L; Department of Clinical Genetics, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK., Shafique A; School of Biological Sciences, University of the Punjab, Lahore 54590, Pakistan., Suri M; UK National Paediatric Ataxia Telangiectasia Clinic, Nottingham University Hospitals NHS Trust, Nottingham, UK.; Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, NG5 1PB, UK., Roze E; Sorbonne University, INSERM, CNRS, Paris Brain Institute, Salpêtrière Hospital/AP-HP, Paris 75013, France., Aguennouz M; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy., Ghizlane Z; Unit of Neuropediatrics and Neurometabolism, Pediatric Department 2, Rabat Children's Hospital, BP 6527 Rabat, Morocco., Saadi SM; Human Molecular Genetics Laboratory, NIBGE-PIEAS, Faisalabad 61010, Pakistan., Fatima A; Department of Biological and Biomedical Sciences, The Aga Khan University, Karachi, Pakistan., Cheema HA; Department of Paediatric Gastroenterology Hepatology and Genetic diseases Children's Hospital and University of Child Health Sciences Lahore  Pakistan., Anjum MN; Department of Paediatric Gastroenterology Hepatology and Genetic diseases Children's Hospital and University of Child Health Sciences Lahore  Pakistan., Morel G; Service de Génétique Médicale, CHU de La Réunion, site Felix Guyon, France., Robin S; Service de Génétique Médicale, CHU de La Réunion, site Felix Guyon, France., McFarland R; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE2 4HH, UK., Altunoglu U; Medical Genetics Department, School of Medicine (KUSoM), Koç University, Istanbul, Turkey., Kraus V; Department of Pediatrics and Social Pediatrics, TUM School of Medicine, ZSE partner site Munich, Munich, Germany., Shoukier M; Department of Molecular Genetics, Prenatal Medicine Munich, Munich, Germany., Murphy D; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK., Flemming K; Department of Pediatric Rehabilitation, University Hospital Northern Norway., Yttervik H; Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway., Rhouda H; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy., Lesca G; Genetics Department, Hospices Civils de Lyon, Lyon, France; GENDEV Team, CRNL, INSERM U1028, CNRS UMR 5292, UCBL1, Lyon, France., Chatron N; Genetics Department, Hospices Civils de Lyon, Lyon, France; GENDEV Team, CRNL, INSERM U1028, CNRS UMR 5292, UCBL1, Lyon, France., Rossi M; Genetics Department, Hospices Civils de Lyon, Lyon, France; GENDEV Team, CRNL, INSERM U1028, CNRS UMR 5292, UCBL1, Lyon, France., Murtaza BN; Abbottabad University of Science and Technology KP, Pakistan Government College University (GCU), Lahore, Pakistan., Ur Rehman M; Abbottabad University of Science and Technology KP, Pakistan Government College University (GCU), Lahore, Pakistan., Lord J; Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, UK., Giacopuzzi E; Technopole, Viale Rita Levi-Montalcini 1, Milan, Italy., Hayat A; Department of MLT, Abbottabad University of Science and Technology KP, Pakistan., Siraj M; Department of Zoology, Abbottabad University of Science and Technology KP, Pakistan., Badv RS; Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Iran., Seo GH; 3billion inc, Seoul, South Korea., Beetz C; Centogene GmbH, Rostock, Germany., Kayserili H; Medical Genetics Department, School of Medicine (KUSoM), Koç University, Istanbul, Turkey., Krioulie Y; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy., Chung WK; Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA., Naz S; School of Biological Sciences, University of the Punjab, Lahore 54590, Pakistan., Maqbool S; Department of Developmental-Behavioral Pediatrics, The Children's Hospital, University of Child Health Sciences (UCHS-CH), Lahore 54600, Pakistan., Chandler K; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK., Kershaw C; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK., Wright T; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Banka S; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Gleeson JG; Department of Neurosciences, University of California, San Diego, La Jolla 92093, USA.; Rady Children's Institute for Genomic Medicine, San Diego 92123, USA., Taylor JC; NIHR Oxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, OX3 9DU, UK., Efthymiou S; Department of Neuromuscular diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK., Baig SM; Department of Biological and Biomedical Sciences, The Aga Khan University, Karachi, Pakistan.; Faculty of Life Sciences, Health Services Academy, Park Road, Islamabad 44000, Pakistan., Severino M; UO Neuroradiologia, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy., Jepson JEC; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK., Houlden H; Department of Neuromuscular diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Dec 18. Date of Electronic Publication: 2024 Dec 18.
DOI:	10.1093/brain/awae363
Abstrakt:	Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects of RBL2 mutations in detail, we identified and clinically characterized a cohort of 35 patients from 20 families carrying pLOF variants in RBL2, including fifteen new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were uniformly observed, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Disrupted sleep was also evident in some patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements, seizures, and non-specific dysmorphic features. Neuroimaging features included cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, Drosophila melanogaster, to investigate how disruption of the conserved RBL2 orthologue Rbf impacts nervous system function and development. We found that Drosophila Rbf LOF mutants recapitulate several features of patients harbouring RBL2 variants, including developmental delay, alterations in head and brain morphology, locomotor defects, and perturbed sleep. Surprisingly, in addition to its known role in controlling tissue growth during development, we found that continued Rbf expression is also required in fully differentiated post-mitotic neurons for normal locomotion in Drosophila, and that adult-stage neuronal re-expression of Rbf is sufficient to rescue Rbf mutant locomotor defects. Taken together, our study provides a clinical and experimental basis to understand genotype-phenotype correlations in an RBL2-linked neurodevelopmental disorder, and suggests that restoring RBL2 expression through gene therapy approaches may ameliorate some symptoms caused by RBL2 pLOF. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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