Entries in CIP (1)

Tuesday
Jun022015

Exciting promise for epigenetic-based pain therapeutics

As a consequence of growing up in Buffalo, NY, I have never adjusted well to high temperatures. This became a bit of a problem in graduate school, when I lived in Baltimore, MD (summer average temperature is around 90F!). One morning I was particularly motivated and went for a jog, it was only 80 degrees; I thought I would be fine!  However, when I was only two miles into my routine (no problem at that time…) I broke out in a cold sweat, became dizzy, and felt instantly nauseous and weak. It was AWFUL! Luckily, I recognized these symptoms and rested in the shade until I could safely walk home. But what if these symptoms didn’t occur? What if I hadn’t felt awful? Likely, I would have suffered a serious heat stroke. Such what-if’s are a constant concern for people with CIP (congenital insensitivity to pain). Without pain, everyday activities become dangerous.

CIP is a rare autosomal recessive genetic disease that results in a complete loss of pain perception1. Patients cannot feel extreme injuries such as a broken bone or a third-degree burn2,3,4. Consequently, continual self-mutilation results in lesions to the tongue, bone deformities, corneal scarring, and neuropathic joints5. Patients also cannot recognize signs of internal illness such as infection4. Therefore, those with CIP must diligently survey themselves to access their health daily.

Recently, Chen et al. discovered a set of CIP-related mutations in the PRDM12 gene5. PRDM12 encodes a SET domain protein expressed in nociceptors (pain-sensing neurons) and is required for nociceptor development5. Unlike most SET domain proteins, PRDM12 does not have intrinsic histone methyltransferase activity; instead PRDM12 recruits G9a to dimethylate histone H3 at the lysine 9 position (H3K9me2)5. CIP-related mutations disrupt G9a recruitment and therefore, the histone-modifying potential of PRDM125. Accordingly, precise localization of H3K9me2 during nociceptor development may be essential for pain sensation.

Although too little pain is dangerous, chronic pain is a huge problem for over 100 million Americans6. Inhibition of PRDM12 may provide a promising target for pain therapeutics. It will be interesting to learn the in vivo effects of PRDM12 inhibition in rodent pain models. As current opioid-based pain medications are highly addictive, new pain management treatments represent a huge medical need.

~TG

1.)  Peddareddygari, Oberoi, and Grewal (2014). Congenital Insensitivity to Pain: A Case Report and Review of the Literature. Case Reports in Neurological Medicine.

2.)  Genetics Home Reference (2012). Congenital Insensitivity to Pain. Retrieved from http://ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain

3.)  ABC News (2013). Meet the Child Who Feels No Pain. Retrieved from http://abcnews.go.com/Health/meet-toddler-feels-pain/story?id=20658484&page=2

4.)  Chen et al. (2015). Transcriptional regulator PRDM12 is essential for human pain perception. Nature Genetics Letters.