Genetic variants in autism-related CNTNAP2 impair axonal growth of cortical neurons - Archive ouverte HAL Access content directly
Journal Articles Human Molecular Genetics Year : 2018

Genetic variants in autism-related CNTNAP2 impair axonal growth of cortical neurons

, (1) , (2) , (2) , , (3) , (4) , (5) , (6) , (5)
1
2
3
4
5
6

Abstract

The CNTNAP2 gene, coding for the cell adhesion glycoprotein Caspr2, is thought to be one of the major susceptibility genes for autism spectrum disorder (ASD). A large number of rare heterozygous missense CNTNAP2 variants have been identified in ASD patients. However, most of them are inherited from an unaffected parent, questioning their clinical significance. In the present study, we evaluate their impact on neurodevelopmental functions of Caspr2 in a heterozygous genetic background. Performing cortical neuron cultures from mouse embryos, we demonstrate that Caspr2 plays a dose-dependent role in axon growth in vitro. Loss of one Cntnap2 allele is sufficient to elicit axonal growth alteration, revealing a situation that may be relevant for CNTNAP2 heterozygosity in ASD patients. Then, we show that the two ASD variants I869T and G731S, which present impaired binding to Contactin2/TAG-1, do not rescue axonal growth deficits. We find that the variant R1119H leading to protein trafficking defects and retention in the endoplasmic reticulum has a dominant-negative effect on heterozygous Cntnap2 cortical neuron axon growth, through oligomerization with wild-type Caspr2. Finally, we identify an additional variant (N407S) with a dominant-negative effect on axon growth although it is well-localized at the membrane and properly binds to Contactin2. Thus, our data identify a new neurodevelopmental function for Caspr2, the dysregulation of which may contribute to clinical manifestations of ASD, and provide evidence that CNTNAP2 heterozygous missense variants may contribute to pathogenicity in ASD, through selective mechanisms.
Fichier principal
Vignette du fichier
CanaliHMG18.pdf (1.46 Mo) Télécharger le fichier
Origin : Publication funded by an institution
Loading...

Dates and versions

hal-01963618 , version 1 (21-12-2018)

Licence

Attribution - CC BY 4.0

Identifiers

Cite

Giorgia Canali, Marta Garcia, Bruno Hivert, Delphine Pinatel, Aline Goullancourt, et al.. Genetic variants in autism-related CNTNAP2 impair axonal growth of cortical neurons. Human Molecular Genetics, 2018, 27 (11), pp.1941-1954. ⟨10.1093/hmg/ddy102⟩. ⟨hal-01963618⟩
110 View
423 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More