Gene linked to sex differences in autism

The study identified mutations in a gene that cause changes to brain cell function. These changes may contribute to the higher prevalence of autism in boys than in girls. Roche Lab/NINDS

Autism spectrum disorder (ASD) is a developmental disorder that affects communication and behavior. Experts estimate that 1 in 54 children has ASD. The disorder occurs in every racial and ethnic group, and across all socioeconomic levels. However, boys are significantly more likely to develop ASD than girls.

A main biological difference between boys and girls is the sex chromosomes. Every cell in our body has two sex chromosomes. Females have two X chromosomes, and males have one X and one Y. Previous studies have linked mutations in a gene called NLGN4 to autism. NLGNs are important for establishing and maintaining synapses, the places where communication signals are sent between brain cells called neurons. Although the gene on the X chromosome (NLGN4X) is 97% identical to that on the Y (NLGN4Y), most of the mutations found thus far have been in NLGN4X.

A team of researchers led by Drs. Thien A. Nguyen and Katherine Roche at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) explored whether differences between NLGN4 on the X and Y chromosome might play a role in some of the observed sex bias in ASD. They analyzed the genes’ activity and the proteins’ function in rat and human cells in the lab. The study was funded by NINDS and NIH’s National Institute of Mental Health (NIMH). Results were published on April 2, 2020, in Neuron.

The researchers found that the NLGN4Y protein is less able to move to the surface of cells compared with NLGN4X, making it less able to form working synapses. Neurons with only NLGN4Y showed deficits in synaptic signaling.

The researchers found that these differences in protein localization and function were due to a single amino acid on NLGN4Y. A cluster of mutations in the region surrounding that amino acid in NLGN4X have been linked to people with ASD and intellectual disability. Neurons with these mutations showed similar deficits to those seen in neurons making NLGN4Y. Further, changing the amino acid on NLGN4Y to match that of normal NLGN4X restored the protein’s function in cells.

In females, when a gene on one chromosome has a mutation, the same gene on the other chromosome can often compensate. However, in males, when there’s not a functionally equivalent gene on the Y chromosome, mutations on the X chromosome can cause disease. This study's findings suggest that when there’s a harmful mutation in NLGN4X, NLGN4Y isn’t able to take over because the protein doesn’t function the same way. This may help explain why males tend to have a greater incidence of NLGN4X-associated ASD than females.     

“We really need to look at NLGN4X and NLGN4Y more carefully,” Thien says. “Mutations in NLGN4X can lead to widespread and potentially very severe effects in brain function, and the role of NLGNY is still unclear.”