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, 123 (2), e249-e253

Microdeletion in a FAAH Pseudogene Identified in a Patient With High Anandamide Concentrations and Pain Insensitivity

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Case Reports

Microdeletion in a FAAH Pseudogene Identified in a Patient With High Anandamide Concentrations and Pain Insensitivity

Abdella M Habib et al. Br J Anaesth.

Abstract

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.

Keywords: anandamide; anxiolytic; endocannabinoids; pain insensitivity; postoperative analgesia.

Figures

Figure 1
Fig 1
(a) Genomic map showing FAAH, FAAH-OUT, and microdeletion. Human chromosome 1 showing the gene footprints of FAAH and FAAH-OUT. Exons are denoted by blue boxes and the direction of transcription shown by arrows. FAAH single-nucleotide polymorphism (SNP) rs324420 maps to Exon 3 (indicated by an asterisk). The 8131 bp microdeletion detected in the patient is shown flanked by Alu repeated sequences (green boxes), which likely predispose the genomic region to rearrangements. The promoter region and Exons 1 and 2 of FAAH-OUT map to the deleted sequence. (b) Genotype summary. The proband carries both the FAAH-OUT microdeletion and the hypomorphic FAAH SNP, and displayed a full hypoalgesic phenotype. Her son carries the FAAH-OUT microdeletion and had a partial hypoalgesic phenotype. Neither the unaffected mother nor daughter carries the microdeletion. (c–f) Circulating anandamide (AEA), palmitoylethanolamide (PEA), oleoylethanolamine (OEA), and 2-arachidonoylglycerol (2-AG) concentrations. Concentrations of AEA, PEA, OEA, and 2-AG were measured by mass spectrometry from blood samples obtained from the patient and four unrelated normal controls. AEA, PEA, and OEA are substrates for FAAH; 2-AG is not. Controls A and B are homozygous wild type for the hypomorphic SNP; Controls C and D are heterozygous carriers. Average values for the controls were AEA (1.2 pmol ml−1), PEA (43.4 pmol ml−1), OEA (5.1 pmol ml−1), and 2-AG (42.2 pmol ml−1), which is consistent with previous data using a similar measurement protocol. Average values for the patient (two measurements) were AEA (2.0 pmol ml−1), PEA (113.1 pmol ml−1), OEA (17.3 pmol ml−1), and 2-AG (45 pmol ml−1).

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