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Canine NAPEPLD-associated models of human myelin disorders.

  • Minor KM Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN, 55108, USA.
  • Letko A Institute of Genetics, University of Bern, Bern, 3001, Switzerland.
  • Becker D Institute of Genetics, University of Bern, Bern, 3001, Switzerland.
  • Drögemüller M Institute of Genetics, University of Bern, Bern, 3001, Switzerland.
  • Mandigers PJJ Department of Clinical Sciences of Companion Animals, Utrecht University, Utrecht, 3508, CM, The Netherlands.
  • Bellekom SR Department of Clinical Sciences of Companion Animals, Utrecht University, Utrecht, 3508, CM, The Netherlands.
  • Leegwater PAJ Department of Clinical Sciences of Companion Animals, Utrecht University, Utrecht, 3508, CM, The Netherlands.
  • Stassen QEM Department of Clinical Sciences of Companion Animals, Utrecht University, Utrecht, 3508, CM, The Netherlands.
  • Putschbach K Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-University, Munich, 80539, Germany.
  • Fischer A Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-University, Munich, 80539, Germany.
  • Flegel T Department of Small Animal Medicine, University of Leipzig, Leipzig, 04103, Germany.
  • Matiasek K Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-University, Munich, 80539, Germany.
  • Ekenstedt KJ Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, 47907, USA.
  • Furrow E Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN, 55108, USA.
  • Patterson EE Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN, 55108, USA.
  • Platt SR Small Animal Medicine and Surgery, University of Georgia, Athens, GA, 30602, USA.
  • Kelly PA Veterinary Sciences Centre, University College Dublin, Dublin, D04 V1W8, Ireland.
  • Cassidy JP Veterinary Sciences Centre, University College Dublin, Dublin, D04 V1W8, Ireland.
  • Shelton GD Department of Pathology, University of California, La Jolla, CA, 92093, USA.
  • Lucot K Department of Population Health and Reproduction, University of California-Davis, Davis, CA, 95616, USA.
  • Bannasch DL Department of Population Health and Reproduction, University of California-Davis, Davis, CA, 95616, USA.
  • Martineau H Pathobiology and Population Sciences, The Royal Veterinary College, North Mymms, AL9 7TA, UK.
  • Muir CF Pathobiology and Population Sciences, The Royal Veterinary College, North Mymms, AL9 7TA, UK.
  • Priestnall SL Pathobiology and Population Sciences, The Royal Veterinary College, North Mymms, AL9 7TA, UK.
  • Henke D Division of Clinical Neurology, University of Bern, Bern, 3001, Switzerland.
  • Oevermann A Division of Neurological Sciences, University of Bern, Bern, 3001, Switzerland.
  • Jagannathan V Institute of Genetics, University of Bern, Bern, 3001, Switzerland.
  • Mickelson JR Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN, 55108, USA.
  • Drögemüller C Institute of Genetics, University of Bern, Bern, 3001, Switzerland. cord.droegemueller@vetsuisse.unibe.ch.
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  • 2018-04-13
Published in:
  • Scientific reports. - 2018
Animals
Demyelinating Diseases
Disease Models, Animal
Dog Diseases
Dogs
Genome-Wide Association Study
Haplotypes
Humans
Leukoencephalopathies
Mutation, Missense
Myelin Sheath
Phospholipase D
Polymorphism, Single Nucleotide
Whole Genome Sequencing
English Canine leukoencephalomyelopathy (LEMP) is a juvenile-onset neurodegenerative disorder of the CNS white matter currently described in Rottweiler and Leonberger dogs. Genome-wide association study (GWAS) allowed us to map LEMP in a Leonberger cohort to dog chromosome 18. Subsequent whole genome re-sequencing of a Leonberger case enabled the identification of a single private homozygous non-synonymous missense variant located in the highly conserved metallo-beta-lactamase domain of the N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD) gene, encoding an enzyme of the endocannabinoid system. We then sequenced this gene in LEMP-affected Rottweilers and identified a different frameshift variant, which is predicted to replace the C-terminal metallo-beta-lactamase domain of the wild type protein. Haplotype analysis of SNP array genotypes revealed that the frameshift variant was present in diverse haplotypes in Rottweilers, and also in Great Danes, indicating an old origin of this second NAPEPLD variant. The identification of different NAPEPLD variants in dog breeds affected by leukoencephalopathies with heterogeneous pathological features, implicates the NAPEPLD enzyme as important in myelin homeostasis, and suggests a novel candidate gene for myelination disorders in people.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/185154
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