PUBLICATION

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
Mattioli, F., Hayot, G., Drouot, N., Isidor, B., Courraud, J., Hinckelmann, M.V., Mau-Them, F.T., Sellier, C., Goldman, A., Telegrafi, A., Boughton, A., Gamble, C., Moutton, S., Quartier, A., Jean, N., Van Ness, P., Grotto, S., Nambot, S., Douglas, G., Si, Y.C., Chelly, J., Shad, Z., Kaplan, E., Dineen, R., Golzio, C., Charlet-Berguerand, N., Mandel, J.L., Piton, A.
ID
ZDB-PUB-200403-141
Date
2020
Source
American journal of human genetics   106(4): 438-452 (Journal)
Registered Authors
Keywords
C-terminal part, KH domains, NOVA2, alternative splicing, autism, de novo mutations, intellectual disability
MeSH Terms
  • Neurons/physiology*
  • Nerve Tissue Proteins/genetics*
  • Frameshift Mutation/genetics*
  • Female
  • RNA Splicing/genetics*
  • Language Development Disorders/genetics
  • Base Sequence/genetics
  • Animals
  • RNA-Binding Proteins/genetics*
  • Alternative Splicing/genetics
  • Mice
  • Male
  • Humans
  • Axon Guidance/genetics
  • Neurodevelopmental Disorders/genetics*
  • Intellectual Disability/genetics
  • Zebrafish/genetics
  • Heterozygote
  • Down-Regulation/genetics
  • Cells, Cultured
  • Muscle Hypotonia/genetics
  • Child, Preschool
(all 22)
PubMed
32197073 Full text @ Am. J. Hum. Genet.
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.
Genes / Markers
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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Citation
Mattioli, F., Hayot, G., Drouot, N., Isidor, B., Courraud, J., Hinckelmann, M.V., Mau-Them, F.T., Sellier, C., Goldman, A., Telegrafi, A., Boughton, A., Gamble, C., Moutton, S., Quartier, A., Jean, N., Van Ness, P., Grotto, S., Nambot, S., Douglas, G., Si, Y.C., Chelly, J., Shad, Z., Kaplan, E., Dineen, R., Golzio, C., Charlet-Berguerand, N., Mandel, J.L., Piton, A. (2020) 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. American journal of human genetics. 106(4):438-452.