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Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism

ABSTRACT: PHARC is a neurodegenerative disease comprising 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 hydrolyse 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 behaviour 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE23151 | GEO | 2010/08/27

SECONDARY ACCESSION(S): PRJNA131569

REPOSITORIES: GEO

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Project description:PHARC is a neurodegenerative disease comprising 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 hydrolyse 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 behaviour 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. Homozygosity mapping using Affymetrix 250K SNP arrays were performed according to the manufacturer's directions on DNA extracted from peripheral blood samples. This accession number contains the data for families 1-5 plus 7 in the article. Supplementary files linked below. The region of interest on chromosome 20 was found using families 1 and 2. The patients in families 3,4 and 5 were then recruited and the patients were homozygous for the same region on chromosome 20 as those in families 1 and 2, showing that all these patients are distantly related. All affected are homozygous for the same mutation. The rest of the chromosomes fall outside the scope of our study. Mutations in ABHD12 Cause the Neurodegenerative Disease PHARC: An Inborn Error of Endocannabinoid Metabolism, Fiskerstrand et al. The American Journal of Human Genetics, 26 August 2010 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B8JDD-50W2K9M-3&_user=6129429&_coverDate=08%2F26%2F2010&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000000150&_version=1&_urlVersion=0&_userid=6129429&md5=234296648f66debd3e2b08e795f2179f

Project description:The endocannabinoid system plays important roles in the modulation of gastrointestinal motility and secretions. These effects are mainly mediated by the activation by the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) of CB1 receptors expressed on cholinergic neurons. Cannabis sativa extracts also perform these activities, through the detection of CB1 receptors by the phytocannabinoids they contain, in particular delta9-tetrahydrocannabinol. CB1 receptors are abundantly expressed at the synaptic terminals of excitatory motor neurons and cholinergic secretomotor neurons and their activation induces prejunctional inhibition of acetylcholine release. It is thought that the endocannabinoids AEA and 2-AG, by activating these receptors, may exert a physiological control on gastrointestinal contractility and secretions. This research hypothesizes that drugs capable of inhibiting the biosynthetic and catabolic enzymes of endocannabinoids, of inhibiting the transmembrane transport of endocannabinoids or of allosterically modulating CB1 receptors induce important regulating effects of basal contractility and excitatory motor responses, induced by activation of neurons intramural cholinergics, of colonic circular smooth muscle. The effects of drugs acting on CB receptors, endocannabinoid biosynthetic and catabolic enzymes and endocannabinoid membrane transporters on basal contractility or induced by neuronal activation of colonic preparations in vitro will be evaluated. The study will enroll patients affected by colorectal cancer to undergo elective resective surgery at any stage, undergoing upfront surgery or after neo-adjuvant therapy with a therapeutic interval greater than 6 weeks. In the selected patients (see inclusion/exclusion criteria), a fresh sample of about 2.5 cm of healthy colon (healthy resection margin) will be taken, which will be taken in the operating room and sent to the laboratory for in vitro study. Expected results: The study is expected to provide new evidence regarding the induction of pharmacological effects by allosteric receptor modulators of CB1 receptors, inhibitors of endocannabinoid biosynthetic and catabolic enzymes, and inhibitors of cannabinoid transporters in the human colon, which may open interesting perspectives regarding the development of new therapeutic strategies for the treatment of constipation, diarrhea and irritable bowel syndrome.

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Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism

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