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  • Here we report a new human


    Here, we report a new human genetic disorder in a patient with hypoalgesia, altered fear and memory symptoms, and a non-anxious disposition. This disorder is attributable to co-inheritance of a microdeletion in a novel pseudogene and a known FAAH hypomorphic SNP. The microdeletion is flanked by repeated sequences that likely predispose the region to genomic rearrangements, as seen in other genomic disorders. Consequently, there are likely to be additional similar individuals in the general population. The likelihood that this disorder has been under-reported is highlighted by the fact that the patient was diagnosed at age 66 yr despite a recurrent history of painless injuries. Lipid profiling in peripheral blood showed significant increases in AEA, OEA, and PEA, which could be further exaggerated in the apexbio calculator and DRG. Further work is needed to understand which FAA is the major contributor to the painless phenotype. The microdeletion removes the promoter and first two exons of FAAH-OUT, but how this disrupts the function of FAAH is still to be elucidated. A hypothesis is that the FAAH-OUT transcript normally functions as a decoy for microRNAs as a result of the high sequence homology, and protects FAAH mRNA from degradation (Supplementary Fig. S7). Alternatively, FAAH-OUT may have an epigenetic role in regulating FAAH transcription, or the deletion removes a critical transcriptional regulatory element.25, 27 Future work will help us to understand whether targeting FAAH-OUT by viral shRNA or gene editing techniques is an effective analgesic/anxiolytic drug development strategy. This patient provides new insights into the role of the endocannabinoid system in analgesia and more specifically on the FAAH genomic locus, and highlights the importance of the adjacent, previously uncharacterised FAAH-OUT gene to pain sensation. Given the previous failure of FAAH-inhibitor analgesic drug trials, this report has significance, as it provides a new route to developing FAAH-related analgesia through targeting of FAAH-OUT.
    Authors' contributions
    Acknowledgements The authors would like to thank the family for participation in this study, and the volunteers for donating blood samples for analyses. The authors thank John N. Wood for helpful discussions and advice throughout this project. The authors also thank Patrick Fox, Hamish Hay, and Louise Reid (Raigmore Hospital, Inverness, UK); Iain Jones (Southern General Hospital, Glasgow, Scotland); and Judith Singleton (Leith Walk Surgery, Edinburgh, UK) for help with blood sampling, and Sylvie Rose (formerly Addenbrooke's Hospital, Cambridge, UK) for help and advice regarding the cytogenetics analyses. The authors thank the Southern Alberta Mass Spectrometry Centre, located in and supported by the Cumming School of Medicine, University of Calgary, for their services in targeted liquid chromatography–tandem mass spectrometry.
    Fatty acid ethanolamines (FAEs), belong to a class of lipid-derived mediators and include: saturated FAEs such as palmitoylethanolamine (PEA), monounsaturated FAEs such as oleoylethanolamine (OEA), and polyunsaturated FAEs such as anandamide (AEA). Over the last decade, FAEs have been identified to induce a wide range of biological responses through several endogenous receptors. Typically, AEA relieves inflammation and pain by stimulating cannabinoid receptors CB/CB and PEA exerts anti-inflammatory and analgesic activities via the peroxisome proliferator-activated receptor α (PPAR-α)., Hence, during recent decades, regulation of the AEA/PEA signaling through the inhibition of relevant biodegradation enzymes has been considered as a potent therapeutic approach to exert anti-nociceptive and anti-inflammatory effects. Fatty acid amide hydrolase (FAAH), a membrane-bound serine hydrolase, is responsible for the principal degradation of AEA., Its binding site comprises three functional channels: a membrane access channel, an acyl-chain binding channel, and a cytosolic port channel, which are relevant to the transport of the substrate to the catalytic site, the accommodation of the acyl chain during catalysis, and the removal of the leaving group after hydrolysis, respectively. Especially, the substrate is surrounded by the catalytic triad (Ser241-Ser217-Lys142), and the oxyanion hole residues (including Ser241, Gly240, Gly239, and Ile238) during the hydrolysis. The nucleophilic hydroxyl group of the Ser241 interacts with the electrophilic carbonyl group of the substrate, which is accompanied by the formation of an acyl-enzyme adduct and the release of ethanolamine., The inhibition of FAAH may result in the decrease of AEA hydrolysis and therefore the elevation of AEA levels, associated with analgesic and anti-inflammatory activities., , ,