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.

Fiche publication


Date publication

mars 2020

Journal

American journal of human genetics

Auteurs

Membres identifiés du Cancéropôle Est :
Pr MANDEL Jean-Louis, Dr CHARLET BERGUERAND Nicolas , Dr NAMBOT Sophie


Tous les auteurs :
Mattioli F, Hayot G, Drouot N, Isidor B, Courraud J, Hinckelmann MV, Mau-Them FT, 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 YC, Chelly J, Shad Z, Kaplan E, Dineen R, Golzio C, Charlet-Berguerand N, Mandel JL, Piton A

Résumé

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.

Mots clés

C-terminal part, KH domains, NOVA2, alternative splicing, autism, de novo mutations, intellectual disability

Référence

Am. J. Hum. Genet.. 2020 Mar 11;: