ABHD12 is a
lysophosphatidylserine (
lysoPS)
lipase responsible for regulation of immune and neurological processes, and shown to act on the
endocannabinoidarachidonoylglycerol (AG) as a
monoacylglycerol lipase.[8][9] 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.[5] Along with
MAGL and
ABHD6, ABHD12 is responsible for 99% of 2-AG hydrolysis in the brain,[7] and has also been shown to act on the 1(3)-AG
isomer.[9] 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.[9][5]
ABHD12
transcription is abundant in the brain, specifically microglia, but has also been identified in peripheral cell types like
macrophages and
osteoclasts.[10] Murine models have shown ABHD12 plays a role in regulation of
lysophosphatidylserine pathways in the brain.[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 demonstrate
cerebellarmicrogliosis,
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.[11] The ABHD -/- murine model shows increased long-chain
lysoPS accumulation in the brain suggesting
lysoPS signalling contributes to PHARC-like
pathology.[11]
Elevated
lysoPS accumulation in ABHD12
knockout mice suggests lysoPS as an
in vivosubstrate of ABHD12.[11] Elevated lysoPS production in ABHD12 null cells from PHARC subjects can be reversed using an inhibitor of
ABHD16A.[20]
^
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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.
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10.1016/j.ophtha.2014.02.008.
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^
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.
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^
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.
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^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.
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