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Transl Psychiatry

Title:		Sexual dimorphism of AMBRA1-related autistic features in human and mouse
Author(s):		Mitjans M; Begemann M; Ju A; Dere E; Wustefeld L; Hofer S; Hassouna I; Balkenhol J; Oliveira B; van der Auwera S; Tammer R; Hammerschmidt K; Volzke H; Homuth G; Cecconi F; Chowdhury K; Grabe H; Frahm J; Boretius S; Dandekar T; Ehrenreich H;
Address:		"Department of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Gottingen, Germany. DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Gottingen, Germany. Department of Psychiatry and Psychotherapy, UMG, Georg-August-University, Gottingen, Germany. Biomedizinische NMR Forschungs GmbH, Max Planck Institute for Biophysical Chemistry, Gottingen, Germany. Department of Bioinformatics, Biocenter, University of Wurzburg, Wurzburg, Germany. Department of Psychiatry and Psychotherapy, University Medicine, and German Center for Neurodegenerative Diseases (DZNE) Greifswald, Greifswald, Germany. Cognitive Ethology Laboratory, German Primate Center, Gottingen, Germany. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany. IRCCS Fondazione Santa Lucia and Department of Biology, University of Rome Tor Vergata, Rome, Italy. Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen, Denmark. Department of Molecular Cell Biology, Max Planck Institute of Biophysical Chemistry, Gottingen, Germany. Department of Functional Imaging, German Primate Center, Leibniz Institute of Primate Research, Gottingen, Germany"
Journal Title:		Transl Psychiatry
Year:		2017
Volume:		20171010
Issue:		10
Page Number:		e1247 -
DOI:		10.1038/tp.2017.213
ISSN/ISBN:		2158-3188 (Electronic) 2158-3188 (Linking)
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"
Keywords:		"Adaptor Proteins, Signal Transducing/*genetics/metabolism Animals Autism Spectrum Disorder/complications/*genetics/metabolism Brain/pathology Female Gene Knockdown Techniques Humans Leukocytes, Mononuclear/metabolism Male Mice, Transgenic Phenotype Polymo;Neuroscience;"
Notes:		"MedlineMitjans, M Begemann, M Ju, A Dere, E Wustefeld, L Hofer, S Hassouna, I Balkenhol, J Oliveira, B van der Auwera, S Tammer, R Hammerschmidt, K Volzke, H Homuth, G Cecconi, F Chowdhury, K Grabe, H Frahm, J Boretius, S Dandekar, T Ehrenreich, H eng Research Support, Non-U.S. Gov't 2017/10/11 Transl Psychiatry. 2017 Oct 10; 7(10):e1247. doi: 10.1038/tp.2017.213"