Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC

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 Andréasson; Nanna D. Rendtorff; Lisbeth Tranebjærg; Michel Koenig; Didier Lacombe; Cyril Goizet; Patrick J. Babin

doi:10.1016/j.nbd.2016.11.008

Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC

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 Andréasson, Nanna D. Rendtorff, Lisbeth Tranebjærg, Michel Koenig, Didier Lacombe, Cyril Goizet, Patrick J. Babin^*

^*Corresponding author af dette arbejde

17 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Neurobiology of Disease
Vol/bind	98
Sider (fra-til)	36-51
Antal sider	16
ISSN	0969-9961
DOI	https://doi.org/10.1016/j.nbd.2016.11.008
Status	Udgivet - feb. 2017

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10.1016/j.nbd.2016.11.008

Citationsformater

Tingaud-Sequeira, A., Raldúa, D., Lavie, J., Mathieu, G., Bordier, M., Knoll-Gellida, A., Rambeau, P., Coupry, I., André, M., Malm, E., Möller, C., Andréasson, S., Rendtorff, N. D., Tranebjærg, L., Koenig, M., Lacombe, D., Goizet, C., & Babin, P. J. (2017). Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC. Neurobiology of Disease, 98, 36-51. https://doi.org/10.1016/j.nbd.2016.11.008

Tingaud-Sequeira, A, Raldúa, D, Lavie, J, Mathieu, G, Bordier, M, Knoll-Gellida, A, Rambeau, P, Coupry, I, André, M, Malm, E, Möller, C, Andréasson, S, Rendtorff, ND, Tranebjærg, L, Koenig, M, Lacombe, D, Goizet, C & Babin, PJ 2017, 'Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC', Neurobiology of Disease, bind 98, s. 36-51. https://doi.org/10.1016/j.nbd.2016.11.008

@article{5d34a8cafcfa485da8fc386d347b0905,

title = "Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC",

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.",

keywords = "ABHD12, Cell and zebrafish models, Demyelinating polyneuropathy, Hearing loss, ataxia, retinitis pigmentosa, Mutations, Neurodegenerative disease, PHARC",

author = "Ang{\`e}le Tingaud-Sequeira and Demetrio Rald{\'u}a and Julie Lavie and Guilaine Mathieu and Magali Bordier and Anja Knoll-Gellida and Pierre Rambeau and Isabelle Coupry and Mich{\`e}le Andr{\'e} and Eva Malm and Claes M{\"o}ller and Sten Andr{\'e}asson and Rendtorff, {Nanna D.} and Lisbeth Tranebj{\ae}rg and Michel Koenig and Didier Lacombe and Cyril Goizet and Babin, {Patrick J.}",

year = "2017",

month = feb,

doi = "10.1016/j.nbd.2016.11.008",

language = "English",

volume = "98",

pages = "36--51",

journal = "Neurobiology of Disease",

issn = "0969-9961",

publisher = "Academic Press",

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TY - JOUR

T1 - Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC

AU - Tingaud-Sequeira, Angèle

AU - Raldúa, Demetrio

AU - Lavie, Julie

AU - Mathieu, Guilaine

AU - Bordier, Magali

AU - Knoll-Gellida, Anja

AU - Rambeau, Pierre

AU - Coupry, Isabelle

AU - André, Michèle

AU - Malm, Eva

AU - Möller, Claes

AU - Andréasson, Sten

AU - Rendtorff, Nanna D.

AU - Tranebjærg, Lisbeth

AU - Koenig, Michel

AU - Lacombe, Didier

AU - Goizet, Cyril

AU - Babin, Patrick J.

PY - 2017/2

Y1 - 2017/2

N2 - 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.

AB - 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.

KW - ABHD12

KW - Cell and zebrafish models

KW - Demyelinating polyneuropathy

KW - Hearing loss, ataxia, retinitis pigmentosa

KW - Mutations

KW - Neurodegenerative disease

KW - PHARC

U2 - 10.1016/j.nbd.2016.11.008

DO - 10.1016/j.nbd.2016.11.008

M3 - Journal article

C2 - 27890673

AN - SCOPUS:85001114593

SN - 0969-9961

VL - 98

SP - 36

EP - 51

JO - Neurobiology of Disease

JF - Neurobiology of Disease

ER -

Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC

Abstract

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