ABHD12

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).

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.

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.