title: Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism.
abstract: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a neurodegenerative disease marked by early-onset cataract and hearing loss, retinitis pigmentosa, and involvement of both the central and peripheral nervous systems, including demyelinating sensorimotor polyneuropathy and cerebellar ataxia. Previously, we mapped this Refsum-like disorder to a 16 Mb region on chromosome 20. Here we report that mutations in the ABHD12 gene cause PHARC disease and we describe the clinical manifestations in a total of 19 patients from four different countries. The ABHD12 enzyme was recently shown to hydrolyze 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors CB1 and CB2. Our data therefore represent an example of an inherited disorder related to endocannabinoid metabolism. The endocannabinoid system is involved in a wide range of physiological processes including neurotransmission, mood, appetite, pain appreciation, addiction behavior, and inflammation, and several potential drugs targeting these pathways are in development for clinical applications. Our findings show that ABHD12 performs essential functions in both the central and peripheral nervous systems and the eye. Any future drug-mediated interference with this enzyme should consider the potential risk of long-term adverse effects.
authors.affiliation: Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. torunn.fiskerstrand@helse-bergen.no
authors.forename: Torunn
authors.initials: T
authors.lastname: Fiskerstrand
authors.forename: Dorra
authors.initials: D
authors.lastname: H'mida-Ben Brahim
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.forename: Abderrahim
authors.initials: A
authors.lastname: M'zahem
authors.forename: Bjørn Ivar
authors.initials: BI
authors.lastname: Haukanes
authors.forename: Nathalie
authors.initials: N
authors.lastname: Drouot
authors.forename: Julian
authors.initials: J
authors.lastname: Zimmermann
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Cole
authors.forename: Christian
authors.initials: C
authors.lastname: Vedeler
authors.forename: Cecilie
authors.initials: C
authors.lastname: Bredrup
authors.forename: Mirna
authors.initials: M
authors.lastname: Assoum
authors.forename: Meriem
authors.initials: M
authors.lastname: Tazir
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.forename: Abdelmadjid
authors.initials: A
authors.lastname: Hamri
authors.forename: Vidar M
authors.initials: VM
authors.lastname: Steen
authors.forename: Helge
authors.initials: H
authors.lastname: Boman
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Bindoff
authors.forename: Michel
authors.initials: M
authors.lastname: Koenig
authors.forename: Per M
authors.initials: PM
authors.lastname: Knappskog
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics; D000293:Adolescent; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002648:Child; D063388:Endocannabinoids; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D008994:Monoacylglycerol Lipases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D055815:Young Adult
chemical_list: D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D012333:RNA, Messenger; C552558:ABHD12 protein, human; C527260:Abhd12 protein, mouse; D008994:Monoacylglycerol Lipases
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