Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC.
Neurobiology of Disease. 2017-02-01; 98: 36-51
DOI: 10.1016/j.nbd.2016.11.008
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1. Neurobiol Dis. 2017 Feb;98:36-51. doi: 10.1016/j.nbd.2016.11.008. Epub 2016 Nov
23.
Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC.
Tingaud-Sequeira A(1), Raldúa D(2), Lavie J(1), Mathieu G(1), Bordier M(3),
Knoll-Gellida A(1), Rambeau P(1), Coupry I(1), André M(1), Malm E(4), Möller
C(5), Andreasson S(4), Rendtorff ND(6), Tranebjærg L(6), Koenig M(7), Lacombe
D(3), Goizet C(3), Babin PJ(8).
Author information:
(1)Univ. Bordeaux, INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM),
F-33076 Bordeaux, France.
(2)IDÆA-CSIC, Barcelona, Spain.
(3)Univ. Bordeaux, INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM),
F-33076 Bordeaux, France; CHU Bordeaux, Hôpital Pellegrin, Service de Génétique
Médicale, Bordeaux, France.
(4)Department of Ophthalmology, Lund University Hospital, Lund, Sweden.
(5)School of Medicine and Health, Örebro University, Sweden.
(6)Department Audiology, Bispebjerg Hospital/Rigshospitalet, Department of
Clinical Genetics, Rigshospitalet/The Kennedy Center, University of Copenhagen,
Institute for Clinical Medicine Copenhagen, Denmark.
(7)Laboratoire de Génétique Moléculaire et unité INSERM UMR_S827, IURC,
Montpellier, France.
(8)Univ. Bordeaux, INSERM U1211, Maladies Rares: Génétique et Métabolisme (MRGM),
F-33076 Bordeaux, France. Electronic address: .
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.
Copyright © 2016 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nbd.2016.11.008
PMID: 27890673 [Indexed for MEDLINE]