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  • Tingaud-Sequeira, AngèleMaladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France (författare)

Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC

  • Artikel/kapitelEngelska2017

Förlag, utgivningsår, omfång ...

  • Elsevier,2017
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:oru-54703
  • https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-54703URI
  • https://doi.org/10.1016/j.nbd.2016.11.008DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • Funding Agencies:Agence Nationale de la Recherche (ANR)  2010BLAN112601/LIGENAXAssociation Francaise contre les Myopathies (AFM)  14879/MNM2 2012Conseil Regional d'Aquitaine (CRA)  2011-0151/LIGENAXPole de competitivite Prod'InnovAssociation Strumpell-Lorrain (ASL)  2011-0135Association Connaitre les syndromes cerebelleux (CSC)French State in the frame of the "Investments for the future" Programme IdEx Bordeaux  ANR-10-IDEX-03-02Lundbeck Foundation  32011Widex ASLinnaeus Centre for Research on Hearing and Deafness (HEAD): Excellence in the field of Cognitive Hearing Science  349-2007-8654
  • 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.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Raldúa, DemetrioIDÆA-CSIC, Barcelona, Spain (författare)
  • Lavie, JulieMaladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France (författare)
  • Mathieu, GuilaineMaladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France (författare)
  • Bordier, MagaliMaladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France; Service de Génétique Médicale, Centre hospitalier universitaire (CHU) Bordeaux, Hôpital Pellegrin, Bordeaux, France (författare)
  • Knoll-Gellida, AnjaMaladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France (författare)
  • Rambeau, PierreMaladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France (författare)
  • Coupry, IsabelleMaladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France (författare)
  • André, MichèleMaladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France (författare)
  • Malm, EvaDepartment of Ophthalmology, Lund University Hospital, Lund, Sweden (författare)
  • Möller, Claes,1950-Örebro universitet,Institutionen för hälsovetenskaper,Region Örebro län(Swepub:oru)cmr (författare)
  • Andreasson, StenDepartment of Ophthalmology, Lund University Hospital, Lund, Sweden (författare)
  • Rendtorff, NannaDepartment Audiology, Region Huvudstaden, Copenhagen, Denmark; Department of Clinical Genetics, The Kennedy Center, Rigshospitalet, Copenhagen, Denmark; Department Audiology, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine Copenhagen, University of Copenhagen, Copenhagen, Denmark (författare)
  • Tranebjaerg, LisbethDepartment Audiology, Region Huvudstaden, Copenhagen, Denmark; Department of Clinical Genetics, The Kennedy Center, Rigshospitalet, Copenhagen, Denmark; Department Audiology, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine Copenhagen, University of Copenhagen, Copenhagen, Denmark (författare)
  • Koenig, MichelLaboratoire de Génétique Moléculaire et unité, INSERM UMR_S827, University Medical Centre of Montpellier (IURC), Montpellier, France (författare)
  • Lacombe, DidierMaladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France; Service de Génétique Médicale, Centre hospitalier universitaire (CHU) Bordeaux, Hôpital Pellegrin, Bordeaux, France (författare)
  • Goizet, CyrilMaladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France; Service de Génétique Médicale, Centre hospitalier universitaire (CHU) Bordeaux, Hôpital Pellegrin, Bordeaux, France (författare)
  • Babin, PatrickMaladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France (författare)
  • Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, FranceIDÆA-CSIC, Barcelona, Spain (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Neurobiology of Disease: Elsevier98, s. 36-510969-99611095-953X

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