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

Brain : a journal of neurology, ISSN: 1460-2156
2024
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Article Description

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.

Bibliographic Details

Gabriel N Aughey; Elisa Cali; Reza Maroofian; Maha S Zaki; Alistair T Pagnamenta; Zafar Ali; Uzma Abdulllah; Fatima Rahman; Lara Menzies; Anum Shafique; Mohnish Suri; Emmanuel Roze; Mohammed Aguennouz; Zouiri Ghizlane; Saadia Maryam Saadi; Ambrin Fatima; Huma Arshad Cheema; Muhammad Nadeem Anjum; Godelieve Morel; Stephanie Robin; Robert McFarland; Umut Altunoglu; Verena Kraus; Moneef Shoukier; David Murphy; Kristina Flemming; Hilde Yttervik; Hajar Rhouda; Gaetan Lesca; Nicolas Chatron; Massimiliano Rossi; Bibi Nazia Murtaza; Mujaddad Ur Rehman; Jenny Lord; Edoardo Giacopuzzi; Azam Hayat; Muhammad Siraj; Abiodun H Bello; Alagoma Iyagba; Alfons Macaya Ruiz; Amira Nabil; Ani Gevorgyan; Anees Muhammad; Belen Pérez-Dueñas; Benigno Monteagudo Sanchez; Biayna Sukhudyan; Blagovesta Marinova Karashova; Burcin Sanlidag; Carmela Scuderi; Chingiz Shashkin; Cleanthe Spanaki; Efthymios Dardiotis; Erin Torti; Ernest Nwazor; Erum Afzal; Eugenia Borgione; Farooq Shaikh; Fuad Al-Mutairi; Gabriella Di Rosa; Gali Heimer; Georgia Xiromerisiou; Gia Melikishvili; Giovanna Morello; Hadil Kathom; Huseyin Per; Hoda Tomoum; Iram Javed; Issam Al-Khawaja; Kairgali Koneyev; Kamran Salayev; Kaminie Moodley; Konstantin Senkevich; Larissa Arning; Liana Fidani; Lolade Taiwo; Maia Beridze; Manizha Ganieva; Mariam Isayan; Mariam Kekenadze; Mayte García-Silva; Michail Vikelis; Nazi Tabatadze; Nazira Zharkynbekova; Nuzhat Noureen Rana; Olapeju Oguntunde; Oluchi Ekenze; Oluwadamilola O Ojo; Osama Atawneh; Paola Nicolaides; Prince Kazadi; Rauan Kaiyrzhanov; Richard Boles; Rima Ibadova; Salvatore Savasta; Samson Khachatryan; Simona Portaro; Stephanie Efthymiou; Sughra Guliyeva; Tanya Stojkovic; Uduak Williams; Ulviyya Guliyeva; Vincenzo Salpietro; Viorica Chelban; Wolfgang Nachbauer; Yahaya Obiabo; Zaruhi Tavadyan; Zhibek Zholdasova; Zomer Sardar; Abdullah Al-Ajmi; Alberto Verrotti; Arn M J M van den Maagdenberg; Barbara Garavaglia; Bru Cormand; Dagmar Timmann; Daniela Avdjieva; Eleni Zamba Papanicolaou; Fowzan S Alkuraya; Gabriella Silvestri; George Koutsis; Giangluigi Marseglia; Halise Neslihan Önemli Mungan; Jatinder S Goraya; Jun Mine; Kolawole Wahab; Massimo Zollo; Mercedes Pineda-Marfa; Mhammed Aguennouz; Michel D Ferrari; Mohamed A Abd El Hamed; Mohamed El Khorassani; Morenikeji Komolafe; Njideka U Okubadejo; Pasquale Striano; Pierangelo Veggiotti; Radka Tincheva; Salman Kirmani; Salvatore Mangano; Sanni Abubakar; Savvas Papacostas; Selina Banu; Shahnaz Ibrahim; Shazia Maqbool; Shen-Yang Lim; Sherifa Ahmed Hamed; Stanislav Groppa; Sylvia Boesch; Tipu Sultan; Yves A Dauvilliers; Dauren Zhumakhanov; Reza Shervin Badv; Go Hun Seo; Christian Beetz; Hülya Kayserili; Yamna Krioulie; Wendy K Chung; Sadaf Naz; Kate Chandler; Christopher Kershaw; Thomas Wright; Siddharth Banka; Joseph G Gleeson; Jenny C Taylor; Shahid Mahmood Baig; Mariasavina Severino; James E C Jepson; Henry Houlden

Oxford University Press (OUP)

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