Dissecting the autism-associated 16p11.2 locus identifies multiple drivers in neuroanatomical phenotypes and unveils a male-specific role for the major vault protein

Kretz, Perrine F., Wagner, Christel, Mikhaleva, Anna, Montillot, Charlotte, Hugel, Sylvain, Morella, Ilaria ORCID: https://orcid.org/0000-0001-5691-5400, Kannan, Meghna, Fischer, Marie-Christine, Milhau, Maxence, Yalcin, Ipek, Brambilla, Riccardo ORCID: https://orcid.org/0000-0003-3569-5706, Selloum, Mohammed, Herault, Yann, Reymond, Alexandre, Collins, Stephan C. and Yalcin, Binnaz 2023. Dissecting the autism-associated 16p11.2 locus identifies multiple drivers in neuroanatomical phenotypes and unveils a male-specific role for the major vault protein. Genome Biology 24 , 261. 10.1186/s13059-023-03092-8

PDF - Published Version Available under License Creative Commons Attribution. Download (3MB)

Abstract

Background Using mouse genetic studies and systematic assessments of brain neuroanatomical phenotypes, we set out to identify which of the 30 genes causes brain defects at the autism-associated 16p11.2 locus. Results We show that multiple genes mapping to this region interact to regulate brain anatomy, with female mice exhibiting far fewer brain neuroanatomical phenotypes. In male mice, among the 13 genes associated with neuroanatomical defects (Mvp, Ppp4c, Zg16, Taok2, Slx1b, Maz, Fam57b, Bola2, Tbx6, Qprt, Spn, Hirip3, and Doc2a), Mvp is the top driver implicated in phenotypes pertaining to brain, cortex, hippocampus, ventricles, and corpus callosum sizes. The major vault protein (MVP), the main component of the vault organelle, is a conserved protein found in eukaryotic cells, yet its function is not understood. Here, we find MVP expression highly specific to the limbic system and show that Mvp regulates neuronal morphology, postnatally and specifically in males. We also recapitulate a previously reported genetic interaction and show that Mvp+/−;Mapk3+/− mice exhibit behavioral deficits, notably decreased anxiety-like traits detected in the elevated plus maze and open field paradigms. Conclusions Our study highlights multiple gene drivers in neuroanatomical phenotypes, interacting with each other through complex relationships. It also provides the first evidence for the involvement of the major vault protein in the regulation of brain size and neuroanatomy, specifically in male mice.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Biosciences Neuroscience and Mental Health Research Institute (NMHRI)
Publisher:	BioMed Central
ISSN:	1474-760X
Date of First Compliant Deposit:	15 November 2023
Date of Acceptance:	18 October 2023
Last Modified:	28 Feb 2024 12:06
URI:	https://orca.cardiff.ac.uk/id/eprint/163936

Actions (repository staff only)

Edit Item