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  Sexual dimorphism of AMBRA1-related autistic features in human and mouse.

Mitjans, M., Begemann, M., Ju, A., Dere, E., Wüstefeld, L., Hofer, S., et al. (2017). Sexual dimorphism of AMBRA1-related autistic features in human and mouse. Translational Psychiatry, 7: e1247. doi:10.1038/tp.2017.213.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-31AF-9 Version Permalink: http://hdl.handle.net/21.11116/0000-0001-3B96-4
Genre: Journal Article

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 Creators:
Mitjans, M., Author
Begemann, M., Author
Ju, A., Author
Dere, E., Author
Wüstefeld, L., Author
Hofer, S.1, Author              
Hassouna, I., Author
Balkenhol, J., Author
Oliveira, B., Author
van der Auwera, S., Author
Tammer, R., Author
Hammerschmidt, K., Author
Volzke, H., Author
Homuth, G., Author
Cecconi, F., Author
Chowdhury, K.2, Author              
Grabe, H., Author
Frahm, J.1, Author              
Boretius, S., Author
Dandekar, T., Author
Ehrenreich, H., Author more..
Affiliations:
1Biomedical NMR Research GmbH, MPI for biophysical chemistry, Max Planck Society, ou_578634              
2Facility of Microarray Analyses, MPI for biophysical chemistry, Max Planck Society, ou_578589              

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 Abstract: Ambra1 is linked to autophagy and neurodevelopment. Heterozygous Ambra1 deficiency induces autism-like behavior in a sexually dimorphic manner. Extraordinarily, autistic features are seen in female mice only, combined with stronger Ambra1 protein reduction in brain compared to males. However, significance of AMBRA1 for autistic phenotypes in humans and, apart from behavior, for other autism-typical features, namely early brain enlargement or increased seizure propensity, has remained unexplored. Here we show in two independent human samples that a single normal AMBRA1 genotype, the intronic SNP rs3802890-AA, is associated with autistic features in women, who also display lower AMBRA1 mRNA expression in peripheral blood mononuclear cells relative to female GG carriers. Located within a non-coding RNA, likely relevant for mRNA and protein interaction, rs3802890 (A versus G allele) may affect its stability through modification of folding, as predicted by in silico analysis. Searching for further autism-relevant characteristics in Ambra1+/− mice, we observe reduced interest of female but not male mutants regarding pheromone signals of the respective other gender in the social intellicage set-up. Moreover, altered pentylentetrazol-induced seizure propensity, an in vivo readout of neuronal excitation–inhibition dysbalance, becomes obvious exclusively in female mutants. Magnetic resonance imaging reveals mild prepubertal brain enlargement in both genders, uncoupling enhanced brain dimensions from the primarily female expression of all other autistic phenotypes investigated here. These data support a role of AMBRA1/Ambra1 partial loss-of-function genotypes for female autistic traits. Moreover, they suggest Ambra1 heterozygous mice as a novel multifaceted and construct-valid genetic mouse model for female autism.

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Language(s): eng - English
 Dates: 2017-10-10
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1038/tp.2017.213
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Title: Translational Psychiatry
Source Genre: Journal
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Pages: 9 Volume / Issue: 7 Sequence Number: e1247 Start / End Page: - Identifier: -