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Functional validati...
Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC
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- Tingaud-Sequeira, Angèle (författare)
- Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France
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- Raldúa, Demetrio (författare)
- IDÆA-CSIC, Barcelona, Spain
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- Lavie, Julie (författare)
- Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France
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- Mathieu, Guilaine (författare)
- Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France
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- Bordier, Magali (författare)
- Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France; Service de Génétique Médicale, Centre hospitalier universitaire (CHU) Bordeaux, Hôpital Pellegrin, Bordeaux, France
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- Knoll-Gellida, Anja (författare)
- Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France
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- Rambeau, Pierre (författare)
- Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France
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- Coupry, Isabelle (författare)
- Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France
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- André, Michèle (författare)
- Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France
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- Malm, Eva (författare)
- Department of Ophthalmology, Lund University Hospital, Lund, Sweden
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- Möller, Claes, 1950- (författare)
- Örebro universitet,Institutionen för hälsovetenskaper,Region Örebro län
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- Andreasson, Sten (författare)
- Department of Ophthalmology, Lund University Hospital, Lund, Sweden
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- Rendtorff, Nanna (författare)
- Department 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
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- Tranebjaerg, Lisbeth (författare)
- Department 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
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- Koenig, Michel (författare)
- Laboratoire de Génétique Moléculaire et unité, INSERM UMR_S827, University Medical Centre of Montpellier (IURC), Montpellier, France
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- Lacombe, Didier (författare)
- Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France; Service de Génétique Médicale, Centre hospitalier universitaire (CHU) Bordeaux, Hôpital Pellegrin, Bordeaux, France
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- Goizet, Cyril (författare)
- Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France; Service de Génétique Médicale, Centre hospitalier universitaire (CHU) Bordeaux, Hôpital Pellegrin, Bordeaux, France
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- Babin, Patrick (författare)
- Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France
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Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ Bordeaux, Bordeaux, France IDÆA-CSIC, Barcelona, Spain (creator_code:org_t)
- Elsevier, 2017
- 2017
- Engelska.
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Ingår i: Neurobiology of Disease. - : Elsevier. - 0969-9961 .- 1095-953X. ; 98, s. 36-51
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
Nyckelord
- Neurodegenerative disease
- PHARC
- ABHD1
- Mutations
- Cell and zebra fish models
- Demyelinating polyneuropathy
- Hearing loss
- ataxia
- retinitis pigmentosa
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Tingaud-Sequeira ...
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Raldúa, Demetrio
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Lavie, Julie
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Mathieu, Guilain ...
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Bordier, Magali
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Knoll-Gellida, A ...
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Rambeau, Pierre
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Coupry, Isabelle
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André, Michèle
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Malm, Eva
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Möller, Claes, 1 ...
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Andreasson, Sten
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Rendtorff, Nanna
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Tranebjaerg, Lis ...
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Koenig, Michel
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Lacombe, Didier
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Goizet, Cyril
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Babin, Patrick
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