ABHD12
Identifiers
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
Gene location (Human) Chr. Chromosome 20 (human)[1] Band 20p11.21 Start 25,294,742bp[1] End 25,390,835bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2|2 G3 Start 150,674,413bp[2] End 150,746,661bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in C1 segment prefrontal cortex body of pancreas left lobe of thyroid gland right lobe of thyroid gland right frontal lobe cingulate gyrus anterior cingulate cortex nucleus accumbens Brodmann area 9 Top expressed in transitional epithelium of urinary bladder superior frontal gyrus primary visual cortex primary motor cortex seminal vesicula dentate gyrus of hippocampal formation granule cell lateral hypothalamus dorsomedial hypothalamic nucleus pontine nuclei cerebellar cortex More reference expression data BioGPS n/a
Gene ontology Molecular function hydrolase activity lysophospholipase activity acylglycerol lipase activity palmitoyl-(protein) hydrolase activity Cellular component integral component of membrane plasma membrane AMPA glutamate receptor complex membrane cytoplasm dendrite cytoplasm Biological process acylglycerol catabolic process phosphatidylserine catabolic process adult walking behavior response to auditory stimulus monoacylglycerol catabolic process glycerophospholipid catabolic process protein depalmitoylation Sources:Amigo /QuickGO
Orthologs Species Human Mouse Entrez 26090 76192 Ensembl ENSG00000100997 ENSMUSG00000032046 UniProt Q8N2K0 Q99LR1 RefSeq (mRNA) NM_001042472 NM_015600 NM_024465 NM_001356549 NM_001356550 RefSeq (protein) NP_001035937 NP_056415 NP_077785 NP_001343478 NP_001343479 Location (UCSC) Chr 20: 25.29 – 25.39 Mb Chr 2: 150.67 – 150.75 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

alpha/beta-Hydrolase domain containing 12 (ABHD12) is aserine hydrolase encoded by theABHD12gene that 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 alysophospholipase andmetabolizeslysophosphatidylserine (LPS).^[6]

ABHD12 is a ≈45kDa integrated membraneglycoprotein, with anactive site proposed to face into the extracellular space.^[7]

Currently, thecrystal structure of ABHD12 is not known.

ABHD12 is alysophosphatidylserine (lysoPS)lipase responsible for regulation of immune and neurological processes, and shown to act on theendocannabinoidarachidonoylglycerol (AG) as amonoacylglycerol lipase.^[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 withMAGL andABHD6, 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-CB2R signalling pathway inmicroglia, and peripheral 2-AG signalling, however this has not been confirmed.^[9][5]

ABHD12transcription is abundant in the brain, specifically microglia, but has also been identified in peripheral cell types likemacrophages andosteoclasts.^[10] Murine models have shown ABHD12 plays a role in regulation oflysophosphatidylserine pathways in the brain.^[11]

Mutations that compromise thecatalytic activity of ABHD12 have been causally linked to the rareneurodegenerative disease PHARC (polyneuropathy, hearing loss,ataxia,retinitis pigmentosa,cataracts)^[10] and a small proportion ofretinitis pigmentosa.^[12][13]

Identification of ABHD12 was first reported in genetic profiling ofautosomal recessiveretinitis pigmentosa in 1995.^[12] In 2010, mutations in ABHD12 were reported as a causal link for theneurodegenerative disease PHARC .^[10]

Mutations in ABHD12 are associated with the rareneurodegenerative disorder PHARC, as well asretinitis pigmentosa.Null mutations have been shown to lead to development of PHARC, while other mutations can result in a range ofphenotypes, from non-syndromicretinal degeneration to 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, fourframeshift and onesplicing mutation.^{[10][14][15][16][17][18][19]} ABHD12missense mutations have been identified in individuals withretinitis pigmentosa, and a growing range ofphenotypes associated with ABHD12 mutations from PHARC to non-syndromicretinal degeneration are being discovered.^[14][18]

In vitro,enzymatic activity of ABHD12 can be eliminated by sitemutation the residuesSerine-246,Aspartate-333, orHistidine-372, which form acatalytic triad in thehydrolase domain.^[9]

Inhibitors of 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]

Theα/β hydrolase domain includinglipasemotif andcatalytic triad is conserved betweenmurine and 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,motor andauditory impairment, alongside elevatedneuroinflammation with progression associated with age. These characteristics are considered PHARC-likephenotypes as a murine model for human PHARC, however the mouse knockout model doesn't demonstrateocular ormyelination defects, or early onset typical of PHARC.^[11] The ABHD -/- murine model shows increased long-chainlysoPS accumulation in the brain suggestinglysoPS signalling contributes to PHARC-likepathology.^[11]

Azebrafishknockdown (+/-) model has been developed which demonstratesophthalmic defects includingmicrophthalmia, lack oflens clarity, and disruptedretina architecture.^[15]

ElevatedlysoPS accumulation in ABHD12knockout mice suggests lysoPS as anin vivosubstrate of ABHD12.^[11] Elevated lysoPS production in ABHD12 null cells from PHARC subjects can be reversed using an inhibitor ofABHD16A.^[20]

In vitro studies demonstrateenzymatic hydrolysis ofmonoacylglycerol long lipid chains by ABHD12. ABHD12 can use both 1(3)-AG and2-AG as substrates at comparableenzymatic rates.^[9]

ABHD12 has been shown to be associated withAMPA typeglutamate receptors in the brains of rats.^[21]

• Fatty acid amide hydrolase
• Serine hydrolase
• Endocannabinoid enhancer

• Genes on human chromosome 20
• Enzymes

• Articles with short description
• Short description matches Wikidata