Canine NAPEPLD-associated models of human myelin disorders

Minor, K. M.; Letko, Anna; Becker, Doreen; Drögemüller, Michaela; Mandigers, P. J. J.; Bellekom, S. R.; Leegwater, P. A. J.; Stassen, Q. E. M.; Putschbach, K.; Fischer, A.; Flegel, T.; Matiasek, K.; Ekenstedt, K. J.; Furrow, E.; Patterson, E. E.; Platt, S. R.; Kelly, P. A.; Cassidy, J. P.; Shelton, G. D.; Lucot, K.; ... (2018). Canine NAPEPLD-associated models of human myelin disorders. Scientific Reports, 8(1), p. 5818. Nature Publishing Group 10.1038/s41598-018-23938-7

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Research Foci > NeuroCenter
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV) > DKV - Clinical Neurology
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV)
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Experimental Clinical Research

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Letko, Anna; Becker, Doreen; Drögemüller, Michaela; Henke, Diana; Oevermann, Anna; Jagannathan, Vidya and Drögemüller, Cord

Subjects:

500 Science > 590 Animals (Zoology)
600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2045-2322

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Cord Drögemüller

Date Deposited:

26 Apr 2018 08:58

Last Modified:

06 Feb 2019 15:11

Publisher DOI:

10.1038/s41598-018-23938-7

PubMed ID:

29643404

BORIS DOI:

10.7892/boris.114658

URI:

https://boris.unibe.ch/id/eprint/114658

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