Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity
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عرض / فتح
اصدار الناشر (تحقق من خيارات الوصول)
تحقق من خيارات الوصول
التاريخ
2019المؤلف
Habib A.M.Okorokov A.L.
Hill M.N.
Bras J.T.
Lee M.-C.
Li S.
Gossage S.J.
van Drimmelen M.
Morena M.
Houlden H.
Ramirez J.D.
Bennett D.L.H.
Srivastava D.
Cox J.J.
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البيانات الوصفية
عرض كامل للتسجيلةالملخص
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. - 2019 The Author(s)
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