Wouldn’t it be nice if we felt no pain? Although lacking the ability to feel pain sounds tempting, considering we could have simply moved on with our lives without going through the hassle of tending to our injuries, the consequences of being painless can be quite devastating. This is not surprising since generating painful sensations is our body’s way of telling us that something is not right and needs attention. Unfortunately, painless people do exist in reality!

Complete insensitivity to painful stimuli including severe injuries such as bone fractures, cuts, burns or corneal abrasions is displayed by people suffering from extreme inherited pain insensitivity (a.k.a congenital hypoalgesia) [1]. In a recent study, Habib et al. have described six such individuals from a family (popularly known as the Marsili family), with a history of insensitivity to otherwise painful injuries since childhood. The most notable symptoms observed included their ability to use broken limbs without feeling any pain, their insensitivity to severe lesions caused by burns and their inability to feel any discomfort while eating large amounts of hot pepper. Using whole exome sequencing it was demonstrated that missense mutation of an evolutionarily conserved arginine at position 1913 to lysine in the putative transcription factor, ZFX2 (Zinc finger homeobox 2) contributed to the pain insensitivity phenotype observed in this family [2, 3].

This observation was strengthened by further studies performed in a BAC transgenic mouse model expressing mutant ZFX2 with the orthologous mouse arginine-1907 to lysine mutation. The ZFX2 mutant mice demonstrated significant levels of insensitivity to noxious heat and mice bearing the highest genomic copies of the BAC displayed maximum tolerance for the heat stimuli. Additionally, DRG (dorsal root ganglion) neurons which have an enhanced expression of ZFX2 showed a reduced response to capsaicin (chili pepper) in the ZFX2 mutant mice compared to wildtype mice. It is intriguing that several genes associated with pain signaling pathways including Gal, Gfra3 and Ptgir with a consensus AG-rich ZFX2 binding motif, were shown to be downregulated in the mutant DRGs, thereby confirming ZFX2’s contribution as a putative transcription factor in the disease process [4, 5, 6, 7].

While congenital hypoalgesia may have severe life-threatening consequences for those suffering from the disease, it has on the other hand proven to be highly instrumental in the identification of potential analgesic drug targets for treating chronic pain [8]. The work described here highlights the role of ZFX2 in perceiving normal levels of pain in healthy individuals and how that can be disrupted by the missense mutation R1913K. Future studies are still needed to determine if targeting ZFX2 or any of the downstream DRG genes might have any beneficial outcome in the treatment of chronic pain.

VectorBuilder

VectorBuilder specializes in BAC recombineering services and can generate the right BAC clone for creating transgenic mice suitable for your projects. The ZFX2 mutant BAC construct described in the above study was generated by VectorBuilder. We can place reporters behind regulatory sequences on your BAC, introduce point mutations into genes of interest, transfer regions of the BAC onto a plasmid, and add drug-selection or visualization markers to the BAC backbone.

References

1. Nahorski MS, et al. New Mendelian disorders of painlessness. Trends Neurosci. 2015; 38(11):712-724.
2. Habib AM, et al. A novel human pain insensitivity disorder caused by a point mutation in ZFHX2. Brain. 2018; 141(2):365-376.
3. Spinsanti G, et al. Quantitative real-time PCR detection of TRPV-1-4 gene expression in human leukocytes from healthy and hyposensitive subjects. Mol Pain. 2008; 4:51.
4. Homes FE, et al. Transgenic overexpression of galanin in the dorsal root ganglion modulates pain-related behavior. Proc Natl Acad Sci U S A. 2003; 100(10):6180-5.
5. Murota H, et al. Artemin causes hypersensitivity to warm sensation, mimicking warmth-provoked pruritus in atopic dermatitis. J Allergy Clin Immunol. 2012; 130(3):671-682.
6. Murata T, et al. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature.1997; 388(6643):678-82.
7. Pulichino AM, et al. Prostacyclin antagonism reduces pain and inflammation in rodent models of hyperalgesia and chronic arthritis. J Pharmacol Exp Ther. 2006; 319(3):1043-50.
8. Goldberg YP, et al. Human Mendelian pain disorders: a key to discovery and validation of novel analgesics. Clin Genet. 2012; 82(4):367-73.