Researchers have identified new genetic candidates that help explain why autism is diagnosed about four times more often in boys than in girls. The study reveals that small changes in the gene MECP2 on the X chromosome might help explain part of this difference.
In the study, published in the American Journal of Human Genetics, the team screened the regulatory regions of the MECP2 gene with a laboratory tool called Massively Parallel Reporter Assay (MPRA). The researchers also screened MECP2 regulatory regions in autistic individuals and tested the genetic variants they identified using the MPRA assays.
The team identified two regulatory regions where male autistic individuals inherited a variant from their unaffected mother that altered regulatory activity. In fac, one of these variants reduced MECP2 expression by approximately 30% in human neurons, a magnitude that produces social deficits, hyperactivity and anxiety-like characteristics in mice. As predicted by the mouse model, the individual was diagnosed with autism and ADH, but had none of the defining characteristics of Rett syndrome.
“These findings, a result of integrating human and animal studies, suggest that MECP2 regulatory variants can contribute to male-biased autism and reveal just the tip of the iceberg, providing a framework for uncovering regulatory variants in other X chromosome neurodevelopmental genes that may contribute to autism’s missing heritability,” said corresponding author Huda Zoghbi, Distinguished Service Professor at Baylor.
Previous studies in mice from the Zoghbi lab and others have taught researchers that MECP2 produces a Goldilocks protein, meaning that it must maintain a "just right" concentration or activity level for a healthy brain. Having too little—about 50% or less of the normal levels—leads to Rett syndrome, while having twice the normal levels causes a different neurodevelopmental condition called MECP2 duplication syndrome.
“Previous studies in mice also showed us that milder changes in MECP2 levels, for instance reducing the expression by 30% or increasing it by 50%, do not cause the more severe features of Rett syndrome or MECP2 duplication syndrome like seizures or motor problems, but lead to autism-like behaviors,” said first author Rebecca Meyer-Schuman, a postdoctoral associate in the Zoghbi lab.
Data from Baylor College of Medicine