ABHD12

ABHD12, or alpha/beta hydrolase domain-containing protein 12, is a human enzyme belonging to the serine hydrolase family of the ABHD (alpha/beta hydrolase domain-containing) enzymes. It is predicted to adopt the characteristic alpha/beta hydrolase fold and contains the catalytic triad typical of lipases and esterases, suggesting serine hydrolase activity.

Biochemically, ABHD12 acts as a lipid hydrolase, preferentially hydrolyzing monoacylglycerols such as 2-arachidonoylglycerol (2-AG) and thereby modulating endocannabinoid signaling and lipid metabolism. It is membrane-associated and localizes to intracellular membranes, with broad tissue expression including brain.

Genetic mutations in ABHD12 cause PHARC syndrome (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, cataracts), an autosomal recessive neurodegenerative disorder. Individuals typically present with sensory ataxia, progressive polyneuropathy, early-onset hearing loss, and retinal degeneration, among other features. The disease reflects loss of ABHD12 function and dysregulated lipid signaling; disease mechanisms likely involve altered endocannabinoid tone and microglial activity.

Beyond PHARC, ABHD12 is studied as a modulator of endocannabinoid signaling. Pharmacological inhibition of ABHD12 elevates levels of 2-AG and other lipids, providing a tool for dissecting lipid signaling pathways and exploring therapeutic hypotheses in pain, inflammation, and neurodegeneration. Ongoing research seeks to define substrate scope, physiological roles, and the full spectrum of clinical implications.