Clinical and genetic characterization of a progressive RBL2-associated neurodevelopmental disorder DOI Creative Commons
Gabriel Aughey, Elisa Calì, Reza Maroofian

et al.

Brain, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 18, 2024

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, date, clinical features have only described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects mutations detail, we identified and clinically characterized cohort 35 patients from 20 families pLOF variants RBL2, including fifteen new substantially broaden molecular spectrum. The presentation affected is range neurological developmental abnormalities. Global delay intellectual disability were uniformly observed, ranging moderate profound involving lack acquisition key motor speech milestones most patients. Disrupted sleep was also evident some Frequent included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements, seizures, non-specific dysmorphic features. Neuroimaging cerebral atrophy, white matter volume loss, corpus callosum hypoplasia cerebellar atrophy. In parallel, used fruit fly, Drosophila melanogaster, investigate how disruption orthologue Rbf impacts nervous system development. We found LOF mutants recapitulate several harbouring variants, delay, alterations head brain morphology, locomotor defects, perturbed sleep. Surprisingly, addition its known role controlling tissue growth development, continued expression required fully differentiated post-mitotic neurons for normal locomotion Drosophila, adult-stage neuronal re-expression sufficient rescue mutant defects. Taken together, our study provides experimental basis understand genotype-phenotype correlations an RBL2-linked disorder, suggests restoring through therapy approaches may ameliorate symptoms caused pLOF.

Language: Английский

Neuropeptide‐Dependent Spike Time Precision and Plasticity in Circadian Output Neurons DOI Creative Commons
Bryan Chong, Vipin Kumar, Dieu Linh Nguyen

et al.

European Journal of Neuroscience, Journal Year: 2025, Volume and Issue: 61(5)

Published: March 1, 2025

ABSTRACT Circadian rhythms influence various physiological and behavioral processes such as sleep–wake cycles, hormone secretion, metabolism. In Drosophila , an important set of circadian output neurons is called pars intercerebralis (PI) neurons, which receive input from specific clock DN1. These DN1 can further be subdivided into functionally anatomically distinctive anterior (DN1a) posterior (DN1p) clusters. The neuropeptide diuretic hormones 31 (Dh31) 44 (Dh44) are the insect neuropeptides known to activate PI control activity rhythms. However, neurophysiological basis how Dh31 Dh44 affect neural coding mechanisms underlying sleep in not well understood. Here, we identify Dh31/Dh44‐dependent spike time precision plasticity neurons. We first find that a mixture enhanced firing compared application alone alone. next synthesized affects membrane potential dynamics precise timing neuronal through their synergistic interaction, possibly mediated by calcium‐activated potassium channel conductance. Further, characterize Dh31/Dh44 enhances postsynaptic potentials Together, these results suggest multiplexed neuropeptide‐dependent .

Language: Английский

Citations

0

Neuropeptide-dependent spike time precision and plasticity in circadian output neurons DOI Creative Commons
Bryan Chong, Vipin Kumar, Dieu Linh Nguyen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 7, 2024

Abstract Circadian rhythms influence various physiological and behavioral processes such as sleep-wake cycles, hormone secretion, metabolism. output neurons are a group of that receive input from the central circadian clock located in suprachiasmatic nucleus mammalian brain transmit timing information to different regions body, coordinating processes. In Drosophila , an important set called pars intercerebralis (PI) neurons, which specific DN1. These can further be subdivided into functionally anatomically distinctive anterior (DN1a) posterior (DN1p) clusters. The neuropeptide diuretic hormones 31 (Dh31) 44 (Dh44) insect neuropeptides known activate PI control activity rhythms. However, neurophysiological basis how Dh31 Dh44 affect neural coding mechanisms underlying sleep is not well understood. Here, we identify Dh31/Dh44-dependent spike time precision plasticity neurons. We find application synthesized affects membrane potential dynamics precise neuronal firing through their synergistic interaction, possibly mediated by calcium-activated potassium channel conductance. Further, characterize Dh31/Dh44 enhances postsynaptic potentials Together, these results suggest multiplexed neuropeptide-dependent .

Language: Английский

Citations

2

Clinical and genetic characterization of a progressive RBL2-associated neurodevelopmental disorder DOI Creative Commons
Gabriel Aughey, Elisa Calì, Reza Maroofian

et al.

Brain, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 18, 2024

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, date, clinical features have only described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects mutations detail, we identified and clinically characterized cohort 35 patients from 20 families pLOF variants RBL2, including fifteen new substantially broaden molecular spectrum. The presentation affected is range neurological developmental abnormalities. Global delay intellectual disability were uniformly observed, ranging moderate profound involving lack acquisition key motor speech milestones most patients. Disrupted sleep was also evident some Frequent included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements, seizures, non-specific dysmorphic features. Neuroimaging cerebral atrophy, white matter volume loss, corpus callosum hypoplasia cerebellar atrophy. In parallel, used fruit fly, Drosophila melanogaster, investigate how disruption orthologue Rbf impacts nervous system development. We found LOF mutants recapitulate several harbouring variants, delay, alterations head brain morphology, locomotor defects, perturbed sleep. Surprisingly, addition its known role controlling tissue growth development, continued expression required fully differentiated post-mitotic neurons for normal locomotion Drosophila, adult-stage neuronal re-expression sufficient rescue mutant defects. Taken together, our study provides experimental basis understand genotype-phenotype correlations an RBL2-linked disorder, suggests restoring through therapy approaches may ameliorate symptoms caused pLOF.

Language: Английский

Citations

0