Clinical and genetic characterization of a progressive <i>RBL2</i>-associated neurodevelopmental disorder

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 been described in only 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 15 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 observed uniformly, 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 might ameliorate some symptoms caused by RBL2 pLOF.

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Brain
Published
2024-12-18
DOI
https://doi.org/10.1093/brain/awae363
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1
Primary Topic
Genetics and Neurodevelopmental Disorders
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article
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0.55

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

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

Gabriel Aughey, Bibi Nazia Murtaza, Jenny C. Taylor, Hajar Rhouda, Jenny Lord, Shazia Maqbool, Zouiri Ghizlane, Maha Saad Zaki, Kristina Flemming, Wendy K. Chung, Stéphanie Robin, M. Aguennouz, Elisa Calì, Lara Menzies, Mohnish Suri, Fatima Rahman, Hülya Kayserili, Stéphanie Efthymiou, Nicolas Chatron, Hilde Yttervik, Emmanuel Flamand Roze, Muhammad Siraj, Massimiliano Rossi, Godeliève Morel, Sadaf Naz, Verena Kraus, Anum Shafique, Moneef Shoukier, Huma Arshad Cheema, Umut Altunoğlu, David Murphy, Gaëtan Lesca, Go Hun Seo, Alistair T. Pagnamenta, Robert McFarland, Mariasavina Severino, Thomas Wright, Ambrin Fatima, Reza Shervin Badv, Shahid Mahmood Baig, Zafar Ali, James E.C. Jepson, Henry Houlden, Reza Maroofian, Saadia Maryam Saadi, Christian Beetz, Christopher J. Kershaw, Edoardo Giacopuzzi, Joseph G. Gleeson, Siddharth Banka, Muhammad Nadeem Anjum, Kate Chandler, Azam Hayat, Mujaddad Ur Rehman, Uzma Abdulllah, Yamna Krioulie
article en
1 citations

Abstract

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 been described in only 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 15 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 observed uniformly, 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 might ameliorate some symptoms caused by RBL2 pLOF.

BrainVol. 148(4)
Université Claude Bernard Lyon 1 (FR), University of Messina (IT), Aga Khan University (PK), Boston Children's Hospital (US), Centre National de la Recherche Scientifique (FR), University Hospital of North Norway (NO), National Institute for Biotechnology and Genetic Engineering (PK), Children’s Institute (US), Nottingham University Hospitals NHS Trust (GB), Centre for Human Genetics (GB), Pakistan Institute of Engineering and Applied Sciences (PK), Koç University (TR), Harvard University (US), Inserm (FR), University of the Punjab (PK), Pohang Iron and Steel (South Korea) (KR), Pir Mehr Ali Shah Arid Agriculture University (PK), Great Ormond Street Hospital for Children NHS Foundation Trust (GB), Istituto Giannina Gaslini (IT), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), Northern Hospital (AU), University of Health Sciences Lahore (PK), University of Manchester (GB), Abbottabad University of Science and Technology (PK), University of Swat (PK), University of California San Diego (US), Sorbonne Université (FR), University of Oxford (GB), Centre Hospitalier Universitaire de La Réunion (RE), Manchester University NHS Foundation Trust (GB), Centre de Recherche en Neurosciences de Lyon (FR), Assistance Publique – Hôpitaux de Paris (FR), École des Hautes Études Commerciales (MA), Hospices Civils de Lyon (FR), Children's Medical Center (IR), Human Technopole (IT), München Klinik (DE), National Research Centre (EG), Centogene (Germany) (DE), Wellcome Centre for Mitochondrial Research (GB), Genomics England (GB), Oxford BioMedica (United Kingdom) (GB), National Hospital for Neurology and Neurosurgery (GB), Institut du Cerveau (FR), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Health Services Academy (PK), Government College University, Lahore (PK), University College London (GB), Technical University of Munich (DE), Tehran University of Medical Sciences (IR), Newcastle University (GB), University of Sheffield (GB)
Michael J. Fox Foundation for Parkinson's Research, Friedreich's Ataxia Research Alliance, Fidelity Foundation, Pakistan Science Foundation, Wellcome Trust, Multiple System Atrophy Coalition, National Institute for Health and Care Research, Guarantors of Brain, University College London, European Commission, Rosetrees Trust, Cerebral Palsy Alliance, National Institutes of Health, Manchester Biomedical Research Centre, Medical Research Council, NIHR Sheffield Biomedical Research Centre
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