Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC

Research output: Contribution to journalArticle

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.

Details

Authors
  • Angèle Tingaud-Sequeira
  • Demetrio Raldúa
  • Julie Lavie
  • Guilaine Mathieu
  • Magali Bordier
  • Anja Knoll-Gellida
  • Pierre Rambeau
  • Isabelle Coupry
  • Michèle André
  • Eva Malm
  • Claes Möller
  • Sten Andreasson
  • Nanna D. Rendtorff
  • Lisbeth Tranebjærg
  • Michel Koenig
  • Didier Lacombe
  • Cyril Goizet
  • Patrick J. Babin
External organisations
  • Skåne University Hospital
  • Örebro University
  • University of Copenhagen
  • University of Bordeaux
  • Centre Hospitalier Universitaire de Bordeaux
  • University of Montpellier
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Neurosciences

Keywords

  • ABHD12, Cell and zebrafish models, Demyelinating polyneuropathy, Hearing loss, ataxia, retinitis pigmentosa, Mutations, Neurodegenerative disease, PHARC
Original languageEnglish
Pages (from-to)36-51
Number of pages16
JournalNeurobiology of Disease
Volume98
Publication statusPublished - 2017 Feb 1
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes