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Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC
Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France.
IDÆA-CSIC, Barcelona, Spain.
Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France.
Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France.
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2017 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 98, p. 36-51Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2017. Vol. 98, p. 36-51
Keywords [en]
Neurodegenerative disease, PHARC, ABHD1, Mutations, Cell and zebra fish models, Demyelinating polyneuropathy, Hearing loss, ataxia, retinitis pigmentosa
National Category
Medical Genetics Cell and Molecular Biology Neurology
Identifiers
URN: urn:nbn:se:oru:diva-54703DOI: 10.1016/j.nbd.2016.11.008ISI: 000394727300004PubMedID: 27890673Scopus ID: 2-s2.0-85001114593OAI: oai:DiVA.org:oru-54703DiVA, id: diva2:1065115
Note

Funding Agencies:

Agence Nationale de la Recherche (ANR)  2010BLAN112601/LIGENAX

Association Francaise contre les Myopathies (AFM)  14879/MNM2 2012

Conseil Regional d'Aquitaine (CRA)  2011-0151/LIGENAX

Pole de competitivite Prod'Innov

Association Strumpell-Lorrain (ASL)  2011-0135

Association Connaitre les syndromes cerebelleux (CSC)

French State in the frame of the "Investments for the future" Programme IdEx Bordeaux  ANR-10-IDEX-03-02

Lundbeck Foundation  32011

Widex AS

Linnaeus Centre for Research on Hearing and Deafness (HEAD): Excellence in the field of Cognitive Hearing Science  349-2007-8654

Available from: 2017-01-13 Created: 2017-01-13 Last updated: 2018-07-30Bibliographically approved

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