Researchers identify specific gene linked to protecting women against autism

In many cases, all it takes is one mutated gene to orchestrate changes across an entire network of genes linked to autism, according to new findings published today in Nature by researchers at Boston Children’s Hospital. This discovery could explain why different mutations in one or more of the hundreds of genes linked to autism can lead to a similar condition. Building on this finding, the researchers also discovered that one gene in particular, ZFX, is at the heart of a well-known effect whereby females are relatively protected against severe autism symptoms, even when they carry mutations associated with autism.

The study’s lead author, Christopher Walsh, MD, PhD, chief of the Division of Genetics and Genomics and a Howard Hughes Medical Institute investigator, and senior authors Rebecca Andersen, PhD and Maya Talukdar, PhD, and their colleagues studied a number of autism-related genes in a human cell model. They observed similar genetic patterns in most cases, regardless of which gene was disrupted.

“The fact is, if you down-regulate one autism gene, you down-regulate a lot of them,” Andersen said. “This ‘transcriptomic convergence,’ as we call it, allows us to understand how hundreds of different genes can cause similar phenotypes, a similar condition.”

New research suggests that many of the various genes that can cause autism when disrupted by rare mutations may actually act in concert. The downregulation of one can regulate many.

The investigators also looked for a possible link to the female protective effect, the observation that autism is four to five times more common in men than in women. It has been proposed that the X chromosome plays a role, but it is more nuanced than that women carry two copies and men carry one. Since women carry two X chromosomes, each cell in the human body turns off most of the genes on one of them to avoid toxicity and cell death. However, there are exceptions: more than sixty genes on the X chromosome escape this “inactivation of the X chromosome”, including the transcriptional activator ZFX. As a result, females have higher expression of ZFX since it is expressed from both of their

“The most important take-home messages are the idea of ​​this transcriptomic convergence in autism and our identification of the ZFX gene as a potential driver of male bias in autism,” Walsh said.

This convergence also suggests that it may be possible to consider therapies that could upregulate many genes associated with autism, rather than having to develop a separate therapy for each of hundreds of genetic mutations, one at a time. Since one gene can regulate many, targeting fewer genes could be effective. For example, up-regulation of ZFX in men could provide them with partial protection against autism closer to that enjoyed by women. Determining a way to increase ZFX levels could also benefit girls, Walsh added. It could be a “rising tide that lifts all boats.”

This work was supported by Autism Speaks Postdoctoral Fellowship 13008 and NIGMS T32 GM007748 (REA); NIH T32 GM007753 and T32 GM144273 (MT); the Simons Foundation Autism Research Initiative, the Howard Hughes Medical Institute, Autism BrainNet (953759), the Yang Tan Collective at Harvard University, the Hock E. Tan and K. Lisa Yang Center for Autism Research at Harvard University. DCP and CAW are investigators from the Howard Hughes Medical Institute.