A study by a team of researchers from the Italian Institute of Technology – IIT in Rovereto, coordinated by Alessandro Gozzi, in collaboration with the Universities of Trento and Pisa, has identified a biological mechanism in preclinical models that would explain why autism is more frequently found in males.
The study, which appeared in Science Advances, provides important new information for basic research in autism, highlighting largely unknown biological mechanisms that contribute to gender prevalence.
Autism spectrum disorders are a varied set of neurodevelopmental disorders characterized by difficulties with communication and social interaction in multiple contexts and types of behaviour. In Italy, it is estimated that about 1 in 77 children (aged 7-9) have an autism spectrum disorder, and the prevalence in males is 4.4 times greater than females (“Progetto Osservatorio per il monitoramento dei disturbi del spectrum autistico”, Observatory for the Monitoring of Autism Spectrum Disorders, a project coordinated by Istituto Superiore di Sanità and the Ministry of Health, last updated 14/03/2024).
The team of researchers identified a new biological mechanism linked to the Ube3a gene, known to the scientific community for encoding a key enzyme in the process of protein degradation. People with a diagnosis of autism often have an overexpression of this gene, and about 1-2% of all autism cases are associated with this type of genetic alteration.
In this study, the researchers demonstrated that the overexpression of Ube3a, in the presence of male sex hormones, triggers a cascade dysregulation mechanism of hundreds of key genes that are involved in autism, comparable to a gene knockout. The multidisciplinary team of researchers conducted analyses on a mouse model with overexpression of the Ube3a gene. Using behavioural tests and MRI brain mapping studies, the researchers found, in a male and female sample, that only males exhibited stereotyped behaviour and connectivity alterations compatible with the autism spectrum. This suggests that the higher prevalence of autism in males is determined by sex-dependent genetic mechanisms.
«Our study demonstrates what has long been suspected: that genetic mechanisms controlled by sex hormones play a crucial role in the imbalance in the diagnosis of autism between males and females» said Alessandro Gozzi, coordinator of the study. «The challenge now is to understand which and how many other mechanisms enhance the risk of autism in males».
«This result is a step forward in understanding the complex genetic puzzle behind autism» explains Michael Lombardo, a researcher at the IIT who participated in the study.
The study involved Alessandro Gozzi, coordinator of IIT’s Centre for Neuroscience and Cognitive Systems (CNCs) in Rovereto, Michael Lombardo, senior researcher at IIT, Yuri Bozzi of the University of Trento (coordinator of the TRAIN-Trentino Autism Initiative strategic project of the University of Trento), Giovanni Provenzano (researcher at the CIBIO Department of the University of Trento) and Massimo Pasqualetti of the University of Pisa. Gozzi and Lombardo conduct research on the brain and neurodivergences thanks to funding from the European Research Council (ERC) and the Simons Foundation Autism Research Initiative (SFARI).
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