A significant difference in the level of RORA protein in the brain tissues of males and females has been identified by a researcher at George Washington University.
Using a genetically identical mouse model, females without autism have a marginally higher level of RORA, the protein encoded by the gene RAR-related orphan receptor A, in the frontal cortex tissue of the brain compared to males without autism.
However, levels of the protein are correspondingly lower in the brain of males as well as females with autism.
Furthermore, the study showed a bigger correlation between the RORA expression level and that of genes regulated by RORA in males.
So, males may be more vulnerable than females to the regulation disruption of multiple genes under conditions of RORA deficiency, these finding suggest.
Valerie Hu, Ph.D., George Washington professor of biochemistry and molecular medicine explains:
“According to the Centers for Disease Control and Prevention, males are nearly four times more likely than females to have autism, but the reason for this sex bias is still a mystery.
Our research suggests that deficiencies in RORA expression in the brain may have a greater impact on males, which may contribute to the known sex bias in autism in several ways."
Novel Candidate Gene
Earlier studies by Hu and her group showed that RORA is a novel candidate gene for autism and is regulated in opposite directions by male and female hormones.
RORA is a nucleic hormone receptor which functions as a transcription factor. It could possibly regulate the transcription of more than 2,500 genes, including over 400 genes known to be associated with autism, they later reported.
This finding suggests a domino effect in which RORA deficiency can impact many autism genes.
Among the genes they confirmed as transcriptional targets of RORA is the gene for aromatase, an enzyme that converts male to female hormones. Therefore, RORA deficiency may lead to aromatase deficiency, which in turn can lead to elevated testosterone levels, one of the proposed risk factors for autism.
“Overall, this study suggests that RORA deficiency may have a greater impact on males, not only because males have lower baseline levels of RORA in the brain to start with, but also because the expression of autism-associated genes may be more highly correlated with the lower expression of RORA in males,” said Hu. “This provides yet another plausible explanation for sex differences in autism susceptibility."
Valerie W Hu et al. Investigation of sex differences in the expression of RORA and its transcriptional targets in the brain as a potential contributor to the sex bias in autism. Molecular Autism, May 2015 DOI: 10.1186/2040-2392-6-7
Illustration: “Protein RORA PDB 1n83” by Emw - Own work. Licensed under CC BY-SA 3.0