TY - JOUR
T1 - Clinical and genetic characterization of a progressive RBL2-associated neurodevelopmental disorder
AU - SYNAPS Study Group
AU - Aughey, Gabriel N
AU - Cali, Elisa
AU - Maroofian, Reza
AU - Zaki, Maha S
AU - Pagnamenta, Alistair T
AU - Ali, Zafar
AU - Abdulllah, Uzma
AU - Rahman, Fatima
AU - Menzies, Lara
AU - Shafique, Anum
AU - Suri, Mohnish
AU - Roze, Emmanuel
AU - Aguennouz, Mohammed
AU - Ghizlane, Zouiri
AU - Saadi, Saadia Maryam
AU - Fatima, Ambrin
AU - Cheema, Huma Arshad
AU - Anjum, Muhammad Nadeem
AU - Morel, Godelieve
AU - Robin, Stephanie
AU - McFarland, Robert
AU - Altunoglu, Umut
AU - Kraus, Verena
AU - Shoukier, Moneef
AU - Flemming, Kristina
AU - Yttervik, Hilde
AU - Rhouda, Hajar
AU - Lesca, Gaetan
AU - Chatron, Nicolas
AU - Rossi, Massimiliano
AU - Murtaza, Bibi Nazia
AU - Ur Rehman, Mujaddad
AU - Lord, Jenny
AU - Giacopuzzi, Edoardo
AU - Hayat, Azam
AU - Siraj, Muhammad
AU - Badv, Reza Shervin
AU - Seo, Go Hun
AU - Beetz, Christian
AU - Kayserili, Hülya
AU - Krioulie, Yamna
AU - Chung, Wendy K
AU - Naz, Sadaf
AU - Maqbool, Shazia
AU - Chandler, Kate
AU - Kershaw, Christopher
AU - Wright, Thomas
AU - Banka, Siddharth
AU - Gleeson, Joseph G
AU - Taylor, Jenny C
N1 - © The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2024/12/18
Y1 - 2024/12/18
N2 - 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.
AB - 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.
U2 - 10.1093/brain/awae363
DO - 10.1093/brain/awae363
M3 - Article
C2 - 39692517
SN - 0006-8950
JO - Brain : a journal of neurology
JF - Brain : a journal of neurology
ER -