Autism, a developmental disorder that causes deficits in social behavior and communication, affects four times as many boys as girls. Because of this extreme gender imbalance, some scientists posit that sex hormones may contribute to the disease. Now researchers have identified for the first time a gene that may help explain the gender discrepancy and underlie some common autism symptoms.
In 2010 biologist Valerie Hu of the George Washington University Medical Center and her colleagues found that brains of people with autism have low levels of a protein produced by a gene called retinoic acid–related orphan receptor-alpha (RORA). Now they report in a study published in PLoS ONE on February 16 that this gene interacts with certain types of estrogen and testosterone found in the brain.
Hu and her team examined neural cells in their lab. They found that RORA controls the production of an enzyme called aromatase, which converts testosterone to estrogen. But in their tests, the presence of testosterone made RORA less active, leading to a decline in aromatase and a buildup of even more testosterone. Estrogen had the opposite effect. In a typical brain the balance of sex hormones regulates RORA activity and keeps hormone levels steady, but any imbalance can be exacerbated by this loop.
Next, the researchers confirmed that brain tissue from donors who had autism indeed contains low amounts of the RORA protein and aromatase. The authors suggest that a deficiency in these molecules causes the chemical loop to spiral out of control, resulting in an accumulation of testosterone that may cause autism. In most females, higher levels of estrogen could be protecting them from the disorder.
In addition to the gender bias, RORA might be implicated in the abnormal routines that characterize autism. For instance, mice that lack this gene fixate on objects and show limited exploratory behavior, similar to individuals with autism. “I don’t think any single gene is going to explain all of the pathology associated with autism, but RORA does explain quite a few of them,” Hu says.