Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Sexual dimorphism of AMBRA1-related autistic features in human and mouse. 2899 20

The extreme male brain theory of autism posits that its male bias is mediated by exaggeration of male-biased sex differences in the expression of autism-associated traits found in typical populations. The theory is supported by extensive phenotypic evidence, but no genes have yet been described with properties that fit its predictions. The autophagy-associated gene AMBRA1 represents one of the top genome-wide "hits" in recent GWAS studies of schizophrenia, shows sex-differential expression, and has been linked with autism risk and traits in humans and mice, especially or exclusively among females. We genotyped the AMBRA1 autism-risk SNP in a population of typical humans who were scored for the dimensional expression of autistic and schizotypal traits. Females, but not males, homozygous for the GG genotype showed a significant increase in score for the single trait, the Autism Quotient-Imagination subscale, that exhibits a strong, significant male bias in typical populations. As such, females with this genotype resembled males for this highly sexually dimorphic, autism-associated phenotype. These findings support the extreme male brain hypothesis and indicate that sex-specific genetic effects can mediate aspects of risk for autism.
Autism Res Treat 2019
PMID:AMBRA1, Autophagy, and the Extreme Male Brain Theory of Autism. 3168 9

Neurodevelopmental disorders (NDDs) such as intellectual disability and autism spectrum disorder consistently show a male bias in prevalence, but it remains unclear why males and females are affected with different frequency. While many behavioral studies of transgenic NDD models have focused only on males, the requirement by the National Institutes of Health to consider sex as a biological variable has promoted the comparison of male and female performance in wild-type and mutant animals. Here, we review examples of rodent models of NDDs in which sex-specific deficits were identified in molecular, physiological, and/or behavioral responses, showing sex differences in susceptibility to disruption of genes mutated in NDDs. Haploinsufficiency in genes involved in mechanisms such as synaptic function (GABRB3 and NRXN1), chromatin remodeling (CHD8, EMHT1, and ADNP), and intracellular signaling (CC2D1A and ERK1) lead to more severe behavioral outcomes in males. However, in the absence of behavioral deficits, females can still present with cellular and electrophysiological changes that could be due to compensatory mechanisms or differential allocation of molecular and cellular functions in the two sexes. By contrasting these findings with mouse models where females are more severely affected (MTHFR and AMBRA1), we propose a framework to approach the study of sex-specific deficits possibly leading to sex bias in NDDs.
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PMID:Molecular causes of sex-specific deficits in rodent models of neurodevelopmental disorders. 3187