Canine NAPEPLD-associated models of human myelin disorders

K. M. Minor; A. Letko; D. Becker; M. Drögemüller; P. J.J. Mandigers; S. R. Bellekom; P. A.J. Leegwater; Q. E.M. Stassen; K. Putschbach; A. Fischer; T. Flegel; K. Matiasek; K. J. Ekenstedt; E. Furrow; E. E. Patterson; S. R. Platt; P. A. Kelly; J. P. Cassidy; G. D. Shelton; K. Lucot; D. L. Bannasch; H. Martineau; C. F. Muir; S. L. Priestnall; D. Henke; A. Oevermann; V. Jagannathan; J. R. Mickelson; C. Drögemüller

doi:10.1038/s41598-018-23938-7

Canine NAPEPLD-associated models of human myelin disorders

K. M. Minor, A. Letko, D. Becker, M. Drögemüller, P. J.J. Mandigers, S. R. Bellekom, P. A.J. Leegwater, Q. E.M. Stassen, K. Putschbach, A. Fischer, T. Flegel, K. Matiasek, K. J. Ekenstedt, E. Furrow, E. E. Patterson, S. R. Platt, P. A. Kelly, J. P. Cassidy, G. D. Shelton, K. LucotD. L. Bannasch, H. Martineau, C. F. Muir, S. L. Priestnall, D. Henke, A. Oevermann, V. Jagannathan, J. R. Mickelson, C. Drögemüller

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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.

Original language	English (US)
Article number	5818
Journal	Scientific reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-23938-7
State	Published - Dec 1 2018

Bibliographical note

Funding Information:
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.

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© 2018 The Author(s).

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Minor, K. M., Letko, A., Becker, D., Drögemüller, M., 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., ... Drögemüller, C. (2018). Canine NAPEPLD-associated models of human myelin disorders. Scientific reports, 8(1), Article 5818. https://doi.org/10.1038/s41598-018-23938-7

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 & Drögemüller, C 2018, 'Canine NAPEPLD-associated models of human myelin disorders', Scientific reports, vol. 8, no. 1, 5818. https://doi.org/10.1038/s41598-018-23938-7

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title = "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.",

author = "Minor, {K. M.} and A. Letko and D. Becker and M. Dr{\"o}gem{\"u}ller and Mandigers, {P. J.J.} and Bellekom, {S. R.} and Leegwater, {P. A.J.} and Stassen, {Q. E.M.} and K. Putschbach and A. Fischer and T. Flegel and K. Matiasek and Ekenstedt, {K. J.} and E. Furrow and Patterson, {E. E.} and Platt, {S. R.} and Kelly, {P. A.} and Cassidy, {J. P.} and Shelton, {G. D.} and K. Lucot and Bannasch, {D. L.} and H. Martineau and Muir, {C. F.} and Priestnall, {S. L.} and D. Henke and A. Oevermann and V. Jagannathan and Mickelson, {J. R.} and C. Dr{\"o}gem{\"u}ller",

note = "Funding Information: The authors are grateful to the dog owners who donated samples and shared pedigree data of their dogs. We thank Nathalie Besuchet Schmutz, Muriel Fragni{\`e}re, 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 Andr{\'e}, Oliver Forman, Steven Friedenberg, Urs Giger, Christophe Hitte, Marjo Hyt{\"o}nen, 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. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = dec,

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doi = "10.1038/s41598-018-23938-7",

language = "English (US)",

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T1 - Canine NAPEPLD-associated models of human myelin disorders

AU - Minor, K. M.

AU - Letko, A.

AU - Becker, D.

AU - Drögemüller, M.

AU - Mandigers, P. J.J.

AU - Bellekom, S. R.

AU - Leegwater, P. A.J.

AU - Stassen, Q. E.M.

AU - Putschbach, K.

AU - Fischer, A.

AU - Flegel, T.

AU - Matiasek, K.

AU - Ekenstedt, K. J.

AU - Furrow, E.

AU - Patterson, E. E.

AU - Platt, S. R.

AU - Kelly, P. A.

AU - Cassidy, J. P.

AU - Shelton, G. D.

AU - Lucot, K.

AU - Bannasch, D. L.

AU - Martineau, H.

AU - Muir, C. F.

AU - Priestnall, S. L.

AU - Henke, D.

AU - Oevermann, A.

AU - Jagannathan, V.

AU - Mickelson, J. R.

AU - Drögemüller, C.

N1 - Funding Information: 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. Publisher Copyright: © 2018 The Author(s).

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N2 - 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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Canine NAPEPLD-associated models of human myelin disorders

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