title: Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC.
abstract: ABHD12 mutations have been linked to neurodegenerative PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract), a rare, progressive, autosomal, recessive disease. Although ABHD12 is suspected to play a role in the lysophosphatidylserine and/or endocannabinoid pathways, its precise functional role(s) leading to PHARC disease had not previously been characterized. Cell and zebrafish models were designed to demonstrate the causal link between an identified new missense mutation p.T253R, characterized in ABHD12 from a young patient, the previously characterized p.T202I and p.R352* mutations, and the associated PHARC. Measuring ABHD12 monoacylglycerol lipase activity in transfected HEK293 cells demonstrated inhibition with mutated isoforms. Both the expression pattern of zebrafish abhd12 and the phenotype of specific antisense morpholino oligonucleotide gene knockdown morphants were consistent with human PHARC hallmarks. High abhd12 transcript levels were found in the optic tectum and tract, colocalized with myelin basic protein, and in the spinal cord. Morphants have myelination defects and concomitant functional deficits, characterized by progressive ataxia and motor skill impairment. A disruption of retina architecture and retinotectal projections was observed, together with an inhibition of lens clarification and a low number of mechanosensory hair cells in the inner ear and lateral line system. The severe phenotypes in abhd12 knockdown morphants were rescued by introducing wild-type human ABHD12 mRNA, but not by mutation-harboring mRNAs. Zebrafish may provide a suitable vertebrate model for ABHD12 insufficiency and the study of functional impairment and potential therapeutic rescue of this rare, neurodegenerative disease.
authors.affiliation: Univ. Bordeaux, INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM), F-33076 Bordeaux, France.
authors.forename: Angèle
authors.initials: A
authors.lastname: Tingaud-Sequeira
authors.affiliation: IDÆA-CSIC, Barcelona, Spain.
authors.forename: Demetrio
authors.initials: D
authors.lastname: Raldúa
authors.affiliation: Univ. Bordeaux, INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM), F-33076 Bordeaux, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Lavie
authors.affiliation: Univ. Bordeaux, INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM), F-33076 Bordeaux, France.
authors.forename: Guilaine
authors.initials: G
authors.lastname: Mathieu
authors.affiliation: Univ. Bordeaux, INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM), F-33076 Bordeaux, France; CHU Bordeaux, Hôpital Pellegrin, Service de Génétique Médicale, Bordeaux, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Bordier
authors.affiliation: Univ. Bordeaux, INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM), F-33076 Bordeaux, France.
authors.forename: Anja
authors.initials: A
authors.lastname: Knoll-Gellida
authors.affiliation: Univ. Bordeaux, INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM), F-33076 Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rambeau
authors.affiliation: Univ. Bordeaux, INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM), F-33076 Bordeaux, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coupry
authors.affiliation: Univ. Bordeaux, INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM), F-33076 Bordeaux, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: André
authors.affiliation: Department of Ophthalmology, Lund University Hospital, Lund, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Malm
authors.affiliation: School of Medicine and Health, Örebro University, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Möller
authors.affiliation: Department of Ophthalmology, Lund University Hospital, Lund, Sweden.
authors.forename: Sten
authors.initials: S
authors.lastname: Andreasson
authors.affiliation: Department Audiology, Bispebjerg Hospital/Rigshospitalet, Department of Clinical Genetics, Rigshospitalet/The Kennedy Center, University of Copenhagen, Institute for Clinical Medicine Copenhagen, Denmark.
authors.forename: Nanna D
authors.initials: ND
authors.lastname: Rendtorff
authors.affiliation: Department Audiology, Bispebjerg Hospital/Rigshospitalet, Department of Clinical Genetics, Rigshospitalet/The Kennedy Center, University of Copenhagen, Institute for Clinical Medicine Copenhagen, Denmark.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Tranebjærg
authors.affiliation: Laboratoire de Génétique Moléculaire et unité INSERM UMR_S827, IURC, Montpellier, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Koenig
authors.affiliation: Univ. Bordeaux, INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM), F-33076 Bordeaux, France; CHU Bordeaux, Hôpital Pellegrin, Service de Génétique Médicale, Bordeaux, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.affiliation: Univ. Bordeaux, INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM), F-33076 Bordeaux, France; CHU Bordeaux, Hôpital Pellegrin, Service de Génétique Médicale, Bordeaux, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.affiliation: Univ. Bordeaux, INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM), F-33076 Bordeaux, France. Electronic address: p.babin@gpp.u-bordeaux1.fr.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Babin
mesh_terms: D000328:Adult; D000818:Animals; D030801:Animals, Genetically Modified; D001259:Ataxia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002386:Cataract / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D023421:Models, Animal; D008994:Monoacylglycerol Lipases / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011115:Polyneuropathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D012677:Sensation / Q000502:physiology; D013550:Swimming / Q000502:physiology; D015027:Zebrafish
chemical_list: D012333:RNA, Messenger; C552558:ABHD12 protein, human; D008994:Monoacylglycerol Lipases
keywords: ABHD12; Cell and zebrafish models; Demyelinating polyneuropathy; Hearing loss, ataxia, retinitis pigmentosa; Mutations; Neurodegenerative disease; PHARC