ABHD12

ABHD12 is a ≈45 kDa integrated membrane glycoprotein, with an active site proposed to face into the extracellular space. Currently, the crystal structure of ABHD12 is not known. == Function ==

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. Murine models have shown ABHD12 plays a role in regulation of lysophosphatidylserine pathways in the brain. == Clinical significance ==

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) == History ==

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 ==

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. In vitro, enzymatic activity of ABHD12 can be eliminated by site mutation the residues Serine-246, Aspartate-333, or Histidine-372, which form a catalytic triad in the hydrolase domain. == Inhibitors ==

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. == Models ==

The α/β hydrolase domain including lipase motif and catalytic triad is conserved between murine and human ABHD12. 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. A zebrafish knockdown (+/-) model has been developed which demonstrates ophthalmic defects including microphthalmia, lack of lens clarity, and disrupted retina architecture. == Interactions ==

Elevated lysoPS accumulation in ABHD12 knockout mice suggests lysoPS as an in vivo substrate of ABHD12. In vitro studies demonstrate enzymatic hydrolysis of monoacylglycerol long lipid chains by ABHD12. ABHD12 can use both 1(3)-AG and 2-AG as substrates at comparable enzymatic rates. == See also ==