Canine NAPEPLD-associated models of human myelin disorders

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.

TSEN54 missense variant in Standard Schnauzers with leukodystrophy

“…The progressive clinical course, the lesions visible in MRI and loss of myelin in the cerebrum seen light microscopically point towards a demyelinating leukodystrophy rather than to a hypomyelinating disease. Although there are many different types of leukodystrophy described in dogs [6][7][8][9][10][11][12][13][14][15], the distribution and also the histopathological appearance of the lesions described in the TSEN54 mutant dogs were different compared to previously described cases of canine leukodystrophy.…”

“…[1][2][3][4] and an additional eight histopathologically confirmed cases from which only formalin-fixed material was available (no. [5][6][7][8][9][10][11][12]. The genotypes at the TSEN54:c.371G>A variant were perfectly associated with the phenotype (P Fisher = 6.1 x 10 −22 ; Table 2).…”

“…Twelve closely related dogs presented clinically and/or histopathologically with leukodystrophy were designated as cases (no. [1][2][3][4][5][6][7][8][9][10][11][12]. The remaining 369 Standard Schnauzers represented population controls, for which there were no records of neurological disease.…”

“…In veterinary medicine, leukodystrophies were described in many different dog breeds, such as leukomyeloencephalopathy in Rottweiler [6][7][8] and Leonberger dogs [9], globoid cell leukodystrophy or Krabbe's disease in West Highland White Terriers [10,11] and Australian Kelpies [12], cavitating leukodystrophy in Dalmatians [13], fibrinoid leukodystrophy or Alexander's disease in a Labrador Retriever [14] and necrotizing myelopathy in Afghan hounds [15]. In some of these diseases an autosomal recessive mode of inheritance was described [11][12][13].…”

“…In some of these diseases an autosomal recessive mode of inheritance was described [11][12][13]. Causative genetic variants have been identified in GFAP (Labrador Retriever, [14]), NAPELD (Leonberger Dogs, [9]), and VPS11 (Rottweiler dogs, [8]). The present study aimed to characterize clinical and pathological features of a new leukodystrophy in Standard Schnauzer puppies and to identify its underlying genetic cause.…”