Abstract |
The neuro-oncological ventral antigen 2 (NOVA2) protein is a major factor regulating neuron-specific alternative splicing (AS), previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia ( POMA). We report here six individuals with de novo frameshift variants in NOVA2 affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait, and abnormal brain MRI. The six variants lead to the same reading frame, adding a common proline rich C-terminal part instead of the last KH RNA binding domain. We detected 41 genes differentially spliced after NOVA2 downregulation in human neural cells. The NOVA2 variant protein shows decreased ability to bind target RNA sequences and to regulate target AS events. It also fails to complement the effect on neurite outgrowth induced by NOVA2 downregulation in vitro and to rescue alterations of retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. Our results suggest a partial loss-of-function mechanism rather than a full heterozygous loss-of-function, although a specific contribution of the novel C-terminal extension cannot be excluded.
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Authors | Francesca Mattioli, Gaelle Hayot, Nathalie Drouot, Bertrand Isidor, Jérémie Courraud, Maria-Victoria Hinckelmann, Frederic Tran Mau-Them, Chantal Sellier, Alica Goldman, Aida Telegrafi, Alicia Boughton, Candace Gamble, Sebastien Moutton, Angélique Quartier, Nolwenn Jean, Paul Van Ness, Sarah Grotto, Sophie Nambot, Ganka Douglas, Yue Cindy Si, Jamel Chelly, Zohra Shad, Elisabeth Kaplan, Richard Dineen, Christelle Golzio, Nicolas Charlet-Berguerand, Jean-Louis Mandel, Amélie Piton |
Journal | American journal of human genetics
(Am J Hum Genet)
Vol. 106
Issue 4
Pg. 438-452
(04 02 2020)
ISSN: 1537-6605 [Electronic] United States |
PMID | 32197073
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- NOVA2 protein, human
- Nerve Tissue Proteins
- Neuro-Oncological Ventral Antigen
- RNA-Binding Proteins
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Topics |
- Alternative Splicing
(genetics)
- Animals
- Axon Guidance
(genetics)
- Base Sequence
(genetics)
- Cells, Cultured
- Child, Preschool
- Down-Regulation
(genetics)
- Female
- Frameshift Mutation
(genetics)
- Heterozygote
- Humans
- Intellectual Disability
(genetics)
- Language Development Disorders
(genetics)
- Male
- Mice
- Muscle Hypotonia
(genetics)
- Nerve Tissue Proteins
(genetics)
- Neuro-Oncological Ventral Antigen
- Neurodevelopmental Disorders
(genetics)
- Neurons
(physiology)
- RNA Splicing
(genetics)
- RNA-Binding Proteins
(genetics)
- Zebrafish
(genetics)
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