Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity
Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity
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DOI：
10.1016/j.bja.2019.02.019
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发表时间：
2019-08-01
影响因子：
9.8
通讯作者：
Cox, James J.
中科院分区：
文献类型：
--
作者：
Habib, Abdella M.;Okorokov, Andrei L.;Cox, James J.
对遗传性疼痛不敏感的罕见家族的研究可以确定新的人类验证的镇痛药物靶点。在这里，一位66岁的女性，在一次通常疼痛的整形外科手部手术（颧骨切除术）后，不需要术后镇痛。进一步的调查显示，他一生都有无痛性损伤的病史，如频繁的割伤和烧伤，据观察愈合很快。我们报告了这种新的疼痛不敏感性疾病的致病突变：共同遗传（i）背根神经节和脑表达假基因FAAH-OUT的微缺失，我们从脂肪酸酰胺水解酶（FAAH）染色体区域克隆;和（ii）FAAH中一个常见的功能性单核苷酸多态性，赋予降低的表达和活性。与正常对照的亚型单核苷酸多态性携带者相比，外周血中anandamide和相关脂肪酸酰胺（棕榈酰乙醇胺和油酰乙醇胺）的循环浓度显著升高，这些脂肪酸酰胺通常都被FAAH降解。遗传发现和循环脂肪酸酰胺升高与内源性大麻素信号增强和FAAH功能丧失所致的表型一致。我们的研究结果突出了FAAH基因组位点先前未知的复杂性，涉及FAAH-OUT，一种新的假基因和长的非编码RNA的表达。这些数据表明，通过靶向FAAH-OUT开发基于FAAH的镇痛的新途径，这可以显着改善术后疼痛和潜在的慢性疼痛和焦虑障碍的治疗。
The study of rare families with inherited pain insensitivity can identify new human-validated analgesic drug targets. Here, a 66-yr-old female presented with nil requirement for postoperative analgesia after a normally painful orthopaedic hand surgery (trapeziectomy). Further investigations revealed a lifelong history of painless injuries, such as frequent cuts and burns, which were observed to heal quickly. We report the causative mutations for this new pain insensitivity disorder: the co-inheritance of (i) a microdeletion in dorsal root ganglia and brain-expressed pseudogene, FAAH-OUT, which we cloned from the fatty-acid amide hydrolase (FAAH) chromosomal region; and (ii) a common functional single-nucleotide polymorphism in FAAH conferring reduced expression and activity. Circulating concentrations of anandamide and related fatty-acid amides (palmitoylethanolamide and oleoylethanolamine) that are all normally degraded by FAAH were significantly elevated in peripheral blood compared with normal control carriers of the hypomorphic single-nucleotide polymorphism. The genetic findings and elevated circulating fatty-acid amides are consistent with a phenotype resulting from enhanced endocannabinoid signalling and a loss of function of FAAH. Our results highlight previously unknown complexity at the FAAH genomic locus involving the expression of FAAH-OUT, a novel pseudogene and long non-coding RNA. These data suggest new routes to develop FAAH-based analgesia by targeting of FAAH-OUT, which could significantly improve the treatment of postoperative pain and potentially chronic pain and anxiety disorders.