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.
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The authors are grateful to the dog owners who donated samples and shared pedigree data of their dogs. We thank Nathalie Besuchet Schmutz, Muriel Fragnière, and Sabrina Schenk for expert technical assistance, the Next Generation Sequencing Platform of the University of Bern for performing the high-throughput sequencing experiments, and the Interfaculty Bioinformatics Unit of the University of Bern for providing computational infrastructure. We thank the Dog Biomedical Variant Database Consortium (Gus Aguirre, Catherine André, Oliver Forman, Steven Friedenberg, Urs Giger, Christophe Hitte, Marjo Hytönen, Tosso Leeb, Hannes Lohi, Cathryn Mellersh, Anita Oberbauer, Jeffrey Schoenebeck, Sheila Schmutz, Claire Wade) for sharing whole genome sequencing data from control dogs and wolves. We also acknowledge all canine researchers who deposited dog whole genome sequencing data into public databases. Partial funding for E.F. was provided by the Office of the Director, National Institutes of Health (NIH) under award number K01OD019912.