De Novo Frameshift Variants in the Neuronal Splicing Factor NOVA2 Result in a Common C-Terminal Extension and Cause a Severe Form of Neurodevelopmental Disorder

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

Publication Date

4-2-2020

Journal

American Journal of Human Genetics

DOI

10.1016/j.ajhg.2020.02.013

PMID

2197073

PMCID

PMC7118572

PubMedCentral® Posted Date

3-19-2020

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Alternative Splicing, Animals, Axon Guidance, Base Sequence, Cells, Cultured, Child, Preschool, Down-Regulation, Female, Frameshift Mutation, Heterozygote, Humans, Intellectual Disability, Language Development Disorders, Male, Mice, Muscle Hypotonia, Nerve Tissue Proteins, Neuro-Oncological Ventral Antigen, Neurodevelopmental Disorders, Neurons, RNA Splicing, RNA-Binding Proteins, Zebrafish, NOVA2, alternative splicing, intellectual disability, de novo mutations, autism, C-terminal part, KH domains

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.