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 for this work

17 Citations (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.

Original language	English
Journal	Neurobiology of Disease
Volume	98
Pages (from-to)	36-51
Number of pages	16
ISSN	0969-9961
DOIs	https://doi.org/10.1016/j.nbd.2016.11.008
Publication status	Published - Feb 2017

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.nbd.2016.11.008

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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, vol. 98, pp. 36-51. https://doi.org/10.1016/j.nbd.2016.11.008

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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.",

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

language = "English",

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journal = "Neurobiology of Disease",

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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

Keywords

UN SDGs

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