Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2
Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2
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DOI：
10.1101/gr.104976.110
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发表时间：
2010-09-01
期刊：
影响因子：
7
通讯作者：
Darvasi, Ariel
中科院分区：
文献类型：
--
作者：
Nissenbaum, Jonathan;Devor, Marshall;Darvasi, Ariel
慢性神经性疼痛受神经病理学、心理社会因素和遗传易感性的影响。关于易感基因的身份知之甚少。使用综合方法，我们发现CACNG2显着影响神经损伤后慢性疼痛的易感性。CACNG 2编码stargazin，这是一种密切参与谷氨酸能AMPA受体运输的蛋白质。该蛋白也可能是一个钙离子通道亚基。CACNG 2此前曾与癫痫有关。最初，在小鼠模型中使用两种精细定位策略（重组后代测试[RPT]和重组近交分离测试[RIST]），我们将疼痛相关的数量性状位点（QTL）（Pain1）定位到15号染色体上的4.2 Mb区间。这个区间包括155个基因。随后，使用生物信息学和全基因组微阵列表达分析来缩小候选者的列表，并最终将Cacng2确定为可能的候选者。对stargazer小鼠（一种Cacng2亚型突变体）的分析为该基因在疼痛处理中的功能作用提供了电生理和行为证据。最后，我们发现人类CACNG2多态性与接受乳房手术的癌症患者队列中的慢性疼痛相关。我们的研究结果提供了关于神经性疼痛遗传基础的新信息，以及对疼痛生理学的新见解，最终可能实现更好的治疗。
Chronic neuropathic pain is affected by specifics of the precipitating neural pathology, psychosocial factors, and by genetic predisposition. Little is known about the identity of predisposing genes. Using an integrative approach, we discovered that CACNG2 significantly affects susceptibility to chronic pain following nerve injury. CACNG2 encodes for stargazin, a protein intimately involved in the trafficking of glutamatergic AMPA receptors. The protein might also be a Ca2+ channel subunit. CACNG2 has previously been implicated in epilepsy. Initially, using two fine-mapping strategies in a mouse model (recombinant progeny testing [RPT] and recombinant inbred segregation test [RIST]), we mapped a pain-related quantitative trait locus (QTL) (Pain1) into a 4.2-Mb interval on chromosome 15. This interval includes 155 genes. Subsequently, bioinformatics and whole-genome microarray expression analysis were used to narrow the list of candidates and ultimately to pinpoint Cacng2 as a likely candidate. Analysis of stargazer mice, a Cacng2 hypomorphic mutant, provided electrophysiological and behavioral evidence for the gene's functional role in pain processing. Finally, we showed that human CACNG2 polymorphisms are associated with chronic pain in a cohort of cancer patients who underwent breast surgery. Our findings provide novel information on the genetic basis of neuropathic pain and new insights into pain physiology that may ultimately enable better treatments.