|, ABHD12A, BEM46L2, C20orf22, PHARC, dJ965G21.2, abhydrolase domain containing 12|
alpha/beta-Hydrolase domain containing 12 (ABHD12) is a serine hydrolase encoded by the ABHD12 gene that participates in the breakdown of the endocannabinoid neurotransmitter 2-arachidonylglycerol (2-AG) in the central nervous system. It is responsible for about 9% of brain 2-AG hydrolysis. Together, ABHD12 along with two other enzymes, monoacylglycerol lipase (MAGL) and ABHD6, control 99% of 2-AG hydrolysis in the brain. ABHD12 also serves as a lysophospholipase and metabolizes lysophosphatidylserine (LPS).
Currently, the crystal structure of ABHD12 is not known.
ABHD12 is a lysophosphatidylserine (lysoPS) lipase responsible for regulation of immune and neurological processes, and shown to act on the endocannabinoid arachidonoylglycerol (AG) as a monoacylglycerol lipase. Endocannabinoids are associated with a range of physiological processes. ABHD12 acts on 2-AG, and accounts for approximately 9% of 2-AG hydrolysis in the brain. Along with MAGL and ABHD6, ABHD12 is responsible for 99% of 2-AG hydrolysis in the brain, and has also been shown to act on the 1(3)-AG isomer. Based on the extracellular face of the ABHD12 active site and its ability to act on multiple isomeric substrates, ABHD12 has been suggested to act as a guard to the extracellular 2-AG-CB2R signalling pathway in microglia, and peripheral 2-AG signalling, however this has not been confirmed.
ABHD12 transcription is abundant in the brain, specifically microglia, but has also been identified in peripheral cell types like macrophages and osteoclasts. Murine models have shown ABHD12 plays a role in regulation of lysophosphatidylserine pathways in the brain.
Mutations that compromise the catalytic activity of ABHD12 have been causally linked to the rare neurodegenerative disease PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, cataracts) and a small proportion of retinitis pigmentosa.
Identification of ABHD12 was first reported in genetic profiling of autosomal recessive retinitis pigmentosa in 1995. In 2010, mutations in ABHD12 were reported as a causal link for the neurodegenerative disease PHARC .
Mutations in ABHD12 are associated with the rare neurodegenerative disorder PHARC, as well as retinitis pigmentosa. Null mutations have been shown to lead to development of PHARC, while other mutations can result in a range of phenotypes, from non-syndromic retinal degeneration to PHARC.
Currently, PHARC has been identified in at least 27 individuals, with 15 identified loss of function variants of ABHD12, comprising four nonsense, four missense, four frameshift and one splicing mutation. ABHD12 missense mutations have been identified in individuals with retinitis pigmentosa, and a growing range of phenotypes associated with ABHD12 mutations from PHARC to non-syndromic retinal degeneration are being discovered.
Inhibitors of ABHD12 have been identified. Orlistat (tetrahydrolipstatin; THL) and methyl arachidonyl fluorophosphonate (MAFP), so-called “universal lipase/serine hydrolase inhibitors” that are extremely non-selective enzyme inhibitors, were found to inhibit ABHD12. Selective reversible inhibitors have also been identified, including betulinic acid, maslinic acid, oleanolic acid, and ursolic acid.
Based on the observation of ABHD12 mutation in PHARC affected subjects, PHARC cell lines have been considered as human models of ABHD12 knockout.
Mouse knockout (ABHD12 -/-) models demonstrate cerebellar microgliosis, motor and auditory impairment, alongside elevated neuroinflammation with progression associated with age. These characteristics are considered PHARC-like phenotypes as a murine model for human PHARC, however the mouse knockout model doesn’t demonstrate ocular or myelination defects, or early onset typical of PHARC. The ABHD -/- murine model shows increased long-chain lysoPS accumulation in the brain suggesting lysoPS signalling contributes to PHARC-like pathology.
Elevated lysoPS accumulation in ABHD12 knockout mice suggests lysoPS as an in vivo substrate of ABHD12. Elevated lysoPS production in ABHD12 null cells from PHARC subjects can be reversed using an inhibitor of ABHD16A.
- GRCh38: Ensembl release 89: ENSG00000100997 – Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000032046 – Ensembl, May 2017
- “Human PubMed Reference:”.
- “Mouse PubMed Reference:”.
- Savinainen JR, Saario SM, Laitinen JT (February 2012). “The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors”. Acta Physiologica. 204 (2): 267–76. doi:10.1111/j.1748-1716.2011.02280.x. PMC 3320662. PMID 21418147.
- Parkkari T, Haavikko R, Laitinen T, Navia-Paldanius D, Rytilahti R, Vaara M, et al. (2014). “Discovery of triterpenoids as reversible inhibitors of α/β-hydrolase domain containing 12 (ABHD12)”. PLOS One. 9 (5): e98286. doi:10.1371/journal.pone.0098286. PMC 4045134. PMID 24879289.
- Blankman JL, Simon GM, Cravatt BF (December 2007). “A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol”. Chemistry & Biology. 14 (12): 1347–56. doi:10.1016/j.chembiol.2007.11.006. PMC 2692834. PMID 18096503.
- Marrs WR, Blankman JL, Horne EA, Thomazeau A, Lin YH, Coy J, et al. (August 2010). “The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors”. Nature Neuroscience. 13 (8): 951–7. doi:10.1038/nn.2601. PMC 2970523. PMID 20657592.
- Fiskerstrand T, H’mida-Ben Brahim D, Johansson S, M’zahem A, Haukanes BI, Drouot N, et al. (September 2010). “Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism”. American Journal of Human Genetics. 87 (3): 410–7. doi:10.1016/j.ajhg.2010.08.002. PMC 2933347. PMID 20797687.
- Blankman JL, Long JZ, Trauger SA, Siuzdak G, Cravatt BF (January 2013). “ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC”. Proceedings of the National Academy of Sciences of the United States of America. 110 (4): 1500–5. doi:10.1073/pnas.1217121110. PMC 3557017. PMID 23297193.
- Ayuso C, Garcia-Sandoval B, Najera C, Valverde D, Carballo M, Antiñolo G, et al. (Spanish Multicentric and Multidisciplinary Group for Research into Retinitis Pigmentosa) (1995). “Retinitis pigmentosa in Spain”. Clinical Genetics. 48 (3): 120–122. doi:10.1111/j.1399-0004.1995.tb04069.x.
- Ali MU, Rahman MS, Cao J, Yuan PX (August 2017). “Genetic characterization and disease mechanism of retinitis pigmentosa; current scenario”. 3 Biotech. 7 (4): 251. doi:10.1007/s13205-017-0878-3. PMC 5515732. PMID 28721681.
- Nishiguchi KM, Avila-Fernandez A, van Huet RA, Corton M, Pérez-Carro R, Martín-Garrido E, et al. (August 2014). “Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration”. Ophthalmology. 121 (8): 1620–7. doi:10.1016/j.ophtha.2014.02.008. PMID 24697911.
- Tingaud-Sequeira A, Raldúa D, Lavie J, Mathieu G, Bordier M, Knoll-Gellida A, et al. (February 2017). “Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC”. Neurobiology of Disease. 98: 36–51. doi:10.1016/j.nbd.2016.11.008. PMID 27890673.
- Eisenberger T, Slim R, Mansour A, Nauck M, Nürnberg G, Nürnberg P, et al. (September 2012). “Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3”. Orphanet Journal of Rare Diseases. 7 (1): 59. doi:10.1186/1750-1172-7-59. PMC 3518140. PMID 22938382.
- Chen DH, Naydenov A, Blankman JL, Mefford HC, Davis M, Sul Y, et al. (December 2013). “Two novel mutations in ABHD12: expansion of the mutation spectrum in PHARC and assessment of their functional effects”. Human Mutation. 34 (12): 1672–8. doi:10.1002/humu.22437. PMC 3855015. PMID 24027063.
- Yoshimura H, Hashimoto T, Murata T, Fukushima K, Sugaya A, Nishio SY, et al. (May 2015). “Novel ABHD12 mutations in PHARC patients: the differential diagnosis of deaf-blindness”. The Annals of Otology, Rhinology, and Laryngology. 124 (1_suppl): 77S–83S. doi:10.1177/0003489415574513. PMID 25743180.
- Frasquet M, Lupo V, Chumillas MJ, Vázquez-Costa JF, Espinós C, Sevilla T (April 2018). “Phenotypical features of two patients diagnosed with PHARC syndrome and carriers of a new homozygous mutation in the ABHD12 gene”. Journal of the Neurological Sciences. 387: 134–138. doi:10.1016/j.jns.2018.02.021. PMID 29571850.
- Kamat SS, Camara K, Parsons WH, Chen DH, Dix MM, Bird TD, et al. (February 2015). “Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay”. Nature Chemical Biology. 11 (2): 164–71. doi:10.1038/nchembio.1721. PMC 4301979. PMID 25580854.
- Schwenk J, Harmel N, Brechet A, Zolles G, Berkefeld H, Müller CS, et al. (May 2012). “High-resolution proteomics unravel architecture and molecular diversity of native AMPA receptor complexes”. Neuron. 74 (4): 621–33. PMID 22632720.