Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC

@article{TingaudSequeira2017FunctionalVO,
  title={Functional validation of ABHD12 mutations in the 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 G. M{\"o}ller and Sten Andreasson and Nanna D. Rendtorff and Lisbeth Tranebj{\ae}rg and Michel Koenig and Didier Lacombe and Cyril Goizet and Patrick J Babin},
  journal={Neurobiology of Disease},
  year={2017},
  volume={98},
  pages={36-51}
}
A complex homozygous mutation in ABHD12 responsible for PHARC syndrome discovered with NGS and review of the literature
TLDR
A new complex homozygous mutation c.379_385delAACTACTinsGATTCCTTATATACCATTGTAGTCTTACTGCTTTTGGTGAACACA (p.Asn127Aspfs*23) is detected in a 36‐year‐old man, which suggests that the involvement of ABHD12 in polyneuropathies is possibly underestimated.
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Zebrafish Models of Autosomal Recessive Ataxias
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The contributions of zebrafish models to the study of autosomal recessive ataxias characteristic phenotypes, behavior, and gene function are discussed, in addition to commenting on possible treatments found in these models.
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The suitability of the developed zebrafish model for screening of molecules with therapeutic value against ACR acute neurotoxicity is supported, and analysis of neurotransmitters profile showed a significant effect on cholinergic and dopaminergic systems.
Elevated Levels of Arachidonic Acid-Derived Lipids Including Prostaglandins and Endocannabinoids Are Present Throughout ABHD12 Knockout Brains: Novel Insights Into the Neurodegenerative Phenotype
TLDR
Levels of bioactive lipids are dynamic throughout adulthood and deleting ABHD12 disrupts the wider lipidome, modulating multiple AA-derived lipids with potential consequences for neuropathology.
Further characterization of the zebrafish model of acrylamide acute neurotoxicity: gait abnormalities and oxidative stress
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The presence of gait abnormalities has been investigated by using ZebraGait, software specifically designed to analyze the kinematics of fish swimming in a water tunnel, and results support the validity of the ACR acute neurotoxicity model developed in adult zebrafish.
Acrylamide acute neurotoxicity in adult zebrafish
TLDR
The metabolomics analysis shows a depletion in the monoamine neurotransmitters, consistent with the comorbid depression and anxiety disorder, in the brain of the exposed fish.
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References

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Two Novel Mutations in ABHD12: Expansion of the Mutation Spectrum in PHARC and Assessment of Their Functional Effects
TLDR
This is the first report of compound heterozygosity in PHARC and the first study to describe how a mutation might affect ABHD12 expression and function.
Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism.
ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC
TLDR
Untargeted metabolomics combined with a genetic mouse model is used to determine that the poorly characterized serine hydrolase α/β-hydrolase domain-containing (ABHD)12, mutations in which cause the human neurodegenerative disorder PHARC, is a principal LPS lipase in the mammalian brain.
Novel ABHD12 Mutations in PHARC Patients
TLDR
It is shown that PHARC has phenotypic variability, even within a family, which is consistent with previous reports, and mutation analysis is a useful tool for confirming the diagnosis.
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