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.
Highlights
The classification of human leukoencephalopathies was initially based upon pathology and biochemistry and has been applied to disorders caused by toxic, acquired vascular, or infectious insults, as well as inherited disorders[1]
As similar myelin disorders are known in people, this study aimed to identify the genetic cause of canine leukoencephalomyelopathy (LEMP) in Leonbergers and Rottweilers as complementary models
Leukoencephalomyelopathy (LEMP) in Leonbergers is associated with the region of N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD) on chromosome 18
Summary
The classification of human leukoencephalopathies was initially based upon pathology and biochemistry and has been applied to disorders caused by toxic, acquired vascular, or infectious insults, as well as inherited disorders[1] This scheme has recently been updated to a case definition of leukodystrophies that refer to 30 distinct disorders with wasting (dystrophy) of the brain’s white matter (leuko) and a consensus definition of heritable white matter disorders based on neuroimaging[1,2]. More than 60 distinct types of genetic leukoencephalopathies (gLE), a recently introduced broader term[1], are associated with white matter lesions in the central nervous system (CNS), and in people these represent a heterogeneous group of disorders with both highly variable clinical and pathologic manifestations[1,4]. Affected dogs present clinically weak and ataxic with loss of conscious proprioception (Supplementary Video S1) These diseases occur in young animals suggesting a hereditary basis. We report the identification of a causative gene for both these forms of canine LEMP that represents a novel candidate gene for human myelin disorders such as gLE disease
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