1. Canine NAPEPLD-associated models of human myelin disorders
- Author
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Minor, KM, Letko, A, Becker, D, Drögemüller, M, Mandigers, PJJ, Bellekom, SR, Leegwater, PAJ, Stassen, QEM, Putschbach, K, Fischer, A, Flegel, T, Matiasek, K, Ekenstedt, KJ, Furrow, E, Patterson, EE, Platt, SR, Kelly, PA, Cassidy, JP, Shelton, GD, Lucot, K, Bannasch, DL, Martineau, H, Muir, CF, Priestnall, SL, Henke, D, Oevermann, A, Jagannathan, V, Mickelson, JR, and Drögemüller, C
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Brain Disorders ,Autoimmune Disease ,Human Genome ,Biotechnology ,Neurosciences ,2.1 Biological and endogenous factors ,Aetiology ,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 - Abstract
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.
- Published
- 2018