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Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC

Tingaud-Sequeira, Angèle; Raldúa, Demetrio; Lavie, Julie; Mathieu, Guilaine; Bordier, Magali; Knoll-Gellida, Anja; Rambeau, Pierre; Coupry, Isabelle; André, Michèle and Malm, Eva LU , et al. (2017) In Neurobiology of Disease 98. p.36-51
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... (More)

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.

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keywords
ABHD12, Cell and zebrafish models, Demyelinating polyneuropathy, Hearing loss, ataxia, retinitis pigmentosa, Mutations, Neurodegenerative disease, PHARC
in
Neurobiology of Disease
volume
98
pages
16 pages
publisher
Elsevier
external identifiers
  • scopus:85001114593
ISSN
0969-9961
DOI
10.1016/j.nbd.2016.11.008
language
English
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no
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ad4911a9-fa37-43c8-88dd-95a7ab3e310d
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2017-02-06 09:53:28
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2018-10-03 10:21:20
@article{ad4911a9-fa37-43c8-88dd-95a7ab3e310d,
  abstract     = {<p>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.</p>},
  author       = {Tingaud-Sequeira, Angèle and Raldúa, Demetrio and Lavie, Julie and Mathieu, Guilaine and Bordier, Magali and Knoll-Gellida, Anja and Rambeau, Pierre and Coupry, Isabelle and André, Michèle and Malm, Eva and Möller, Claes and Andreasson, Sten and Rendtorff, Nanna D. and Tranebjærg, Lisbeth and Koenig, Michel and Lacombe, Didier and Goizet, Cyril and Babin, Patrick J.},
  issn         = {0969-9961},
  keyword      = {ABHD12,Cell and zebrafish models,Demyelinating polyneuropathy,Hearing loss, ataxia, retinitis pigmentosa,Mutations,Neurodegenerative disease,PHARC},
  language     = {eng},
  month        = {02},
  pages        = {36--51},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC},
  url          = {http://dx.doi.org/10.1016/j.nbd.2016.11.008},
  volume       = {98},
  year         = {2017},
}