Saturday, July 13, 2013

The Gene That Roared—is RORA a “Master Autism Gene”?

Dr. Valerie Hu* is researching metabolic pathways implicated in autism.
I’ve written about Valerie Hu’s work before.  Dr. Hu is originally from Hawaii and is currently a molecular biologist at George Washington University (GWU).  She is passionate about researching metabolic pathways for autism.  Finding these pathways can lead to possible symptom amelioration or even a cure…and one key reason Dr. Hu is passionate about her work is because her own son is severely afflicted by autism.  Knowing autism firsthand is to witness your child suffering on a daily basis, unable to communicate and frequently in pain.  

Dr. Hu has been researching a gene called Retinoic acid-related Orphan Receptor-Alpha (RORA), which controls the production of an enzyme called aromatase, which converts testosterone to estrogen.  In 2010, Dr. Hu and her colleagues found that the brains of autistic people have low levels of a protein produced by the RORA gene and that RORA interacts with types of testosterone and estrogen found in the brain.
How RORA works...
From Psychology Today: RORA is involved in several key processes implicated in autism, including brain cell (Purkinje) differentiation; muscle tone and development of the cerebellum; protection of neurons against chemical stress; suppression of inflammation; and regulation of circadian rhythm.  In research on twins published last year, the expression of RORA was indeed shown to be affected by a key epigenetic factor (methylation).  This explains how one pair of otherwise identical twins can be autistic but the other not. Although identical twins may share the same genes, they may vary in their expression. 

In Dr. Hu's tests, the presence of testosterone made RORA less active, which led to a loop of aromatase levels declining thereby increasing testosterone accumulation; estrogen had the opposite effect.  This gene may explain the extreme gender imbalance in autism occurrence; boys are affected 4 to 5 times more often than girls. Dr. Hu postulated that higher levels of estrogen in girls may help to protect them from developing autism. 

In her latest research, recently published in Molecular Autism, Dr. Hu and her co-author Dr. Tewarit Sarachana found that RORA encodes a protein that can regulate the expression of over 2,500 other genes, and of these genes, many are known to affect neuronal development and functions.  Neurons are electrically excitable cells that are the building blocks of the central nervous system, processing and transmitting information.

What is particularly exciting is 426 of RORA’s gene targets are already listed in AutismKB, a database of known autism candidate genes.  I won’t pretend to understand the scientific techniques Drs. Hu and Sarachana used, but they were able to confirm through their testing that RORA does regulate six genes, and when RORA levels are cut in half, these genes also reduce their expression.  Further, the expression levels of these six genes were confirmed to be reduced in their expression in RORA-deficient post-mortem brain tissues from individuals with autism when compared with age-matched, non-autistic controls.

Dr. Hu says, “We see it as a domino effect, where RORA is a particularly shaky domino.  If knocked over, it can also knock down a whole bunch of other genes, except that it’s not just a single chain of events.  There are multiple chains of events, leading to massive disruption of gene expression in autism.”

Dr. Hu’s work is promising for several reasons.  If the pathways that are disrupted in autism are understood, there is hope for a cure.
My son is not a burden, but his autism burdens him leaving him frustrated and in pain.
I’ve had folks from the neurodiversity crowd tell me children with autism aren’t suffering and that it’s simply a differently-wired brain that does not need to be cured, so before anyone goes there let me say I’m not talking about high-functioning autism here.  I’m talking about the kids who are NOT quirky geniuses who think in pictures, but rather those who suffer with painful gastrointestinal symptoms, epileptic seizures, mitochondrial disorders, autoimmune conditions such as mastocytosis and diabetes, and severe allergies.  Those who are unable to communicate their basic needs…who are not toilet trained.  These kids do suffer--mine included. 

* Dr. Hu received her Ph.D. in Chemistry from Caltech and did her postdoctoral research in Membrane Biochemistry and Immunology at UCLA.  More information about her research and papers can be obtained at: 


Sarachana T., Xu M,. Wu R.C., Hu V.W. (2011). Sex hormones in autism: androgens and estrogens differentially and reciprocally regulate RORA, a novel candidate gene for autism. PLoS One. 2011;4:e17116. doi: 10.1371/journal.pone.0017116.

Sarachana, T. & Hu, V. (2013). Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder. Molecular Autism. 2013. doi:10.1186/2040-2392-4-14.

Xu, L.M., Li, J.R., Huang, Y., Zhao, M., Tang, X. & Wei, L. (2012). AutismKB: an evidence-based knowledgebase of autism genetics. Nucleic Acids Res, 40, D1016-1022. 

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