Mutations Help to Explain Sex Difference in Autism Incidence

Researchers have discovered that a single amino acid change in the NLGN4 gene, which has been linked to autism symptoms, may help to explain why autism spectrum disorder (ASD) is more common in males than in females. The findings were published April 2, 2020 in the journal Neuron.

Using biochemistry, electrophysiology, and imaging, the researchers compared two NLGN4 genes (one on the X chromosome and one on the Y chromosome), which play an important role in the establishment and maintenance of synapses. They discovered that the proteins encoded by these genes display different functions. The NLGN4Y protein is less able to move to the brain cell surface and is therefore unable to assemble and maintain synapses, making it difficult for neurons to send signals to one another. 

The deficits associated with NLGN4Y are due to a single amino acid difference, the researchers found. The researchers also discovered that the region surrounding that amino acid in NLGN4X is sensitive to mutations in the human population. There are a cluster of variants found in this region in people with ASD and intellectual disability and these mutations result in a deficit in function for NLGN4X that is indistinguishable from NLGN4Y. In females, when one of the NLGN4X genes has a mutation, the other one can often compensate. However, in males, diseases can occur when there is a mutation in NLGN4X because there is no compensation by NLGN4Y.

The inability of NLGN4Y to compensate for mutations in NLGN4X may help explain why males, who only have one X chromosome, tend to have a greater incidence of NLGN4X-associated ASD than females