Wouldn’t it be nice if we舞歌 felt no pain? Although lacking the a刀村bility to feel pain soun費會ds tempting, considering we co著輛uld have simply moved on wi花微th our lives wi海紅thout going thro河畫ugh the hassle of tending to our人都 injuries, the consequences of 睡妹being painless can be quite devastatin山光g. This is not surprising since gener還西ating painful sens唱窗ations is our body’s way of telling 錯很us that something is not r校子ight and needs at照器tention. Unfortunately, painless peopl事謝e do exist in reality!
Complete insensitivity to pain山女ful stimuli including severe injuries 事劇such as bone fractures, cuts, bur多車ns or corneal abrasio裡商ns is displayed by people 去船suffering from extreme inherited 討水pain insensitivity (a.k.關樹a congenital hypoa對愛lgesia) [1]. In a recent study媽計, Habib et al. have described是人 six such individuals from a fam筆術ily (popularly known歌生 as the Marsili family), w費低ith a history of insensitiv下員ity to otherwise painful injuries sinc姐煙e childhood. The海快 most notable sympt書一oms observed included their ab吧熱ility to use broken limb年輛s without feeling any pain水飛, their insensitivity to severe lesion音腦s caused by burns and their 輛快inability to fee習就l any discomfort while eatin玩南g large amounts of hot pep的路per. Using whole exom線謝e sequencing it was demonstrated tha輛歌t missense mutati熱坐on of an evolutionari員吧ly conserved arginine at position 1913房睡 to lysine in the putative transcri暗腦ption factor, ZF路雨X2 (Zinc finger homeobox 2) co如雨ntributed to the pain insens做美itivity phenotype observed in this fami看站ly [2, 3].
This observation w友電as strengthened by問什 further studies performed in 購資a BAC transgenic mouse model express畫呢ing mutant ZFX2 with 年科the orthologous mo森他use arginine-1907 to lysine mutat土做ion. The ZFX2 mutant mic水拍e demonstrated significant lev費月els of insensitivity t輛為o noxious heat an哥吃d mice bearing the highest gen吃的omic copies of t間站he BAC displayed maximum 少化tolerance for t機商he heat stimuli. A要就dditionally, DRG (dorsal root ganglion低議) neurons which have an enhance低服d expression of ZFX2 showed a r光工educed response to capsai門頻cin (chili pepper) in 說線the ZFX2 mutant mice compared to w海錯ildtype mice. It is intrigui劇妹ng that several genes associated 章很with pain signaling 他道pathways including Gal市靜, Gfra3 and Ptgi拿匠r with a consensus AG-rich市技 ZFX2 binding moti票村f, were shown to b報學e downregulated i靜厭n the mutant DRGs, thereby con要照firming ZFX2’s contribution玩吃 as a putative transcripti樂們on factor in the 笑風disease process [4, 5, 6,器麗 7].
While congenital hypoal日業gesia may have severe l子工ife-threatening consequences for th不美ose suffering from the disease算愛, it has on the other han姐事d proven to be highly instrumen錢裡tal in the identification of p訊多otential analgesic drug targets fo員話r treating chronic pain [8]. 答也The work described here學的 highlights the role of ZFX2 in p作視erceiving normal lev科光els of pain in healthy individuals and通議 how that can be disrupted by the mi司雨ssense mutation R1913K. Future studies 劇看are still needed to determ新電ine if targeting ZFX2 or any of t綠什he downstream DRG genes might have 多日any beneficial o理司utcome in the treatment o購友f chronic pain.
VectorBuilder specializes in BAC r姐錯ecombineering services金信 and can genera老機te the right BAC c朋喝lone for creating transgenic mice放你 suitable for you友黑r projects. The ZFX2 老看mutant BAC construct descri到信bed in the above study was generated b厭紙y VectorBuilder. We can pl門民ace reporters b下兒ehind regulatory seque司化nces on your BAC, intr多做oduce point mutations into genes of訊東 interest, transfer 少遠regions of the BAC onto a pla書好smid, and add drug-selection or visu視件alization markers to the市刀 BAC backbone.
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