ABHD12
| ABHD12 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | ABHD12,ABHD12A, BEM46L2, C20orf22, PHARC, dJ965G21.2, abhydrolase domain containing 12, habhydrolase domain containing 12, lysophospholipase | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:613599;MGI:1923442;HomoloGene:22910;GeneCards:ABHD12;OMA:ABHD12 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Alpha /beta-Hydrolase domain containing 12(ABHD12) is aserine hydrolaseencoded by theABHD12genethat participates in the breakdown of theendocannabinoidneurotransmitter2-arachidonylglycerol(2-AG) in thecentral nervous system.[5]It is responsible for about 9% of brain 2-AG hydrolysis.[5]Together, ABHD12 along with two other enzymes,monoacylglycerol lipase(MAGL) andABHD6,control 99% of 2-AG hydrolysis in the brain.[5]ABHD12 also serves as alysophospholipaseandmetabolizeslysophosphatidylserine(LPS).[6]
Protein structure
[edit]ABHD12 is a ≈45kDaintegrated membraneglycoprotein,with anactive siteproposed to face into the extracellular space.[7]
Currently, thecrystal structureof ABHD12 is not known.
Function
[edit]ABHD12 is alysophosphatidylserine(lysoPS)lipaseresponsible for regulation of immune and neurological processes, and shown to act on theendocannabinoidarachidonoylglycerol(AG) as amonoacylglycerollipase.[8][9]Endocannabinoids are associated with a range of physiological processes. ABHD12 acts on2-AG,and accounts for approximately 9% of 2-AG hydrolysis in the brain.[5]Along withMAGLandABHD6,ABHD12 is responsible for 99% of 2-AG hydrolysis in the brain,[7]and has also been shown to act on the 1(3)-AGisomer.[9]Based on the extracellular face of the ABHD12 active site and its ability to act on multiple isomericsubstrates,ABHD12 has been suggested to act as a guard to the extracellular 2-AG-CB2Rsignalling pathway inmicroglia,and peripheral 2-AG signalling, however this has not been confirmed.[9][5]
ABHD12transcriptionis abundant in the brain, specifically microglia, but has also been identified in peripheral cell types likemacrophagesandosteoclasts.[10]Murine models have shown ABHD12 plays a role in regulation oflysophosphatidylserinepathways in the brain.[11]
Clinical significance
[edit]Mutations that compromise thecatalytic activityof ABHD12 have been causally linked to the rareneurodegenerativedisease PHARC (polyneuropathy,hearing loss,ataxia,retinitis pigmentosa,cataracts)[10]and a small proportion ofretinitis pigmentosa.[12][13]
History
[edit]Identification of ABHD12 was first reported in genetic profiling ofautosomal recessiveretinitis pigmentosain 1995.[12]In 2010, mutations in ABHD12 were reported as a causal link for theneurodegenerativedisease PHARC.[10]
Mutations
[edit]Mutations in ABHD12 are associated with the rareneurodegenerativedisorder PHARC, as well asretinitis pigmentosa.Null mutationshave been shown to lead to development of PHARC, while other mutations can result in a range ofphenotypes,from non-syndromicretinal degenerationto PHARC.[14]
Currently, PHARC has been identified in at least 27 individuals, with 15 identified loss of function variants of ABHD12,[15]comprising fournonsense,fourmissense,fourframeshiftand onesplicingmutation.[10][14][15][16][17][18][19]ABHD12missensemutations have been identified in individuals withretinitis pigmentosa,and a growing range ofphenotypesassociated with ABHD12 mutations from PHARC to non-syndromicretinal degenerationare being discovered.[14][18]
In vitro,enzymatic activityof ABHD12 can be eliminated by sitemutationthe residuesSerine-246,Aspartate-333, orHistidine-372, which form acatalytic triadin thehydrolasedomain.[9]
Inhibitors
[edit]Inhibitorsof ABHD12 have been identified.[6]Orlistat(tetrahydrolipstatin; THL) andmethyl arachidonyl fluorophosphonate(MAFP), so-called "universal lipase/serine hydrolase inhibitors" that are extremely non-selective enzyme inhibitors, were found to inhibit ABHD12.[6]Selective reversible inhibitors have also been identified, includingbetulinic acid,maslinic acid,oleanolic acid,andursolic acid.[6]
Models
[edit]Theα/β hydrolasedomain includinglipasemotifandcatalytic triadis conserved betweenmurineand human ABHD12.[11]
Based on the observation of ABHD12 mutation in PHARC affected subjects, PHARC cell lines have been considered as human models of ABHD12 knockout.[10]
Mouse knockout(ABHD12 -/-) models demonstratecerebellarmicrogliosis,motorandauditory impairment,alongside elevatedneuroinflammationwith progression associated with age. These characteristics are considered PHARC-likephenotypesas a murine model for human PHARC, however the mouse knockout model doesn't demonstrateocularormyelinationdefects, or early onset typical of PHARC.[11]The ABHD -/- murine model shows increased long-chainlysoPSaccumulation in the brain suggestinglysoPSsignalling contributes to PHARC-likepathology.[11]
Azebrafishknockdown(+/-) model has been developed which demonstratesophthalmicdefects includingmicrophthalmia,lack oflensclarity, and disruptedretina architecture.[15]
Interactions
[edit]ElevatedlysoPSaccumulation in ABHD12knockout micesuggests lysoPS as anin vivosubstrateof ABHD12.[11]Elevated lysoPS production in ABHD12 null cells from PHARC subjects can be reversed using an inhibitor ofABHD16A.[20]
In vitrostudies demonstrateenzymatic hydrolysisofmonoacylglycerollong lipid chains by ABHD12. ABHD12 can use both 1(3)-AG and2-AGas substrates at comparableenzymatic rates.[9]
ABHD12 has been shown to be associated withAMPAtypeglutamate receptorsin the brains of rats.[21]
See also
[edit]References
[edit]- ^abcGRCh38: Ensembl release 89: ENSG00000100997–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000032046–Ensembl,May 2017
- ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^abcdeSavinainen 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.PMC3320662.PMID21418147.
- ^abcdParkkari 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.Bibcode:2014PLoSO...998286P.doi:10.1371/journal.pone.0098286.PMC4045134.PMID24879289.
- ^abBlankman 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.PMC2692834.PMID18096503.
- ^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.PMC2970523.PMID20657592.
- ^abcdeFiskerstrand 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.PMC2933347.PMID20797687.
- ^abcdeBlankman 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.Bibcode:2013PNAS..110.1500B.doi:10.1073/pnas.1217121110.PMC3557017.PMID23297193.
- ^abAyuso 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.S2CID85403725.
- ^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.PMC5515732.PMID28721681.
- ^abcNishiguchi 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.PMID24697911.
- ^abcTingaud-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.PMID27890673.S2CID207070270.
- ^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.PMC3518140.PMID22938382.
- ^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.PMC3855015.PMID24027063.
- ^abYoshimura 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.PMID25743180.S2CID23734319.
- ^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.PMID29571850.S2CID4234582.
- ^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.PMC4301979.PMID25580854.
- ^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.doi:10.1016/j.neuron.2012.03.034.PMID22632720.