{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:52:35Z","timestamp":1787003555831,"version":"build-2736575974"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,4,11]],"date-time":"2018-04-11T00:00:00Z","timestamp":1523404800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,4,11]],"date-time":"2018-04-11T00:00:00Z","timestamp":1523404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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                    <jats:italic>N-acyl phosphatidylethanolamine phospholipase D<\/jats:italic>\n                    (\n                    <jats:italic>NAPEPLD<\/jats:italic>\n                    ) 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\n                    <jats:italic>NAPEPLD<\/jats:italic>\n                    variant. The identification of different\n                    <jats:italic>NAPEPLD<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41598-018-23938-7","type":"journal-article","created":{"date-parts":[[2018,4,11]],"date-time":"2018-04-11T10:42:57Z","timestamp":1523443377000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Canine NAPEPLD-associated models of human myelin disorders"],"prefix":"10.1038","volume":"8","author":[{"given":"K. M.","family":"Minor","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Letko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Dr\u00f6gem\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2547-6673","authenticated-orcid":false,"given":"P. J. J.","family":"Mandigers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. R.","family":"Bellekom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. A. J.","family":"Leegwater","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Q. E. M.","family":"Stassen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Putschbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Flegel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Matiasek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. J.","family":"Ekenstedt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Furrow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. E.","family":"Patterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. R.","family":"Platt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. A.","family":"Kelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. P.","family":"Cassidy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. D.","family":"Shelton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Lucot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. L.","family":"Bannasch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Martineau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. F.","family":"Muir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. L.","family":"Priestnall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Henke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Oevermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"Jagannathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. R.","family":"Mickelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9773-522X","authenticated-orcid":false,"given":"C.","family":"Dr\u00f6gem\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,4,11]]},"reference":[{"key":"23938_CR1","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1016\/j.ymgme.2015.01.006","volume":"114","author":"A Vanderver","year":"2015","unstructured":"Vanderver, A. et al. Case definition and classification of leukodystrophies and leukoencephalopathies. Mol. Genet. Metab. 114, 494\u2013500 (2015).","journal-title":"Mol. Genet. Metab."},{"key":"23938_CR2","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1002\/ajmg.b.30029","volume":"129B","author":"M Di Rocco","year":"2004","unstructured":"Di Rocco, M., Biancheri, R., Rossi, A., Filocamo, M. & Tortori-Donati, P. Genetic disorders affecting white matter in the pediatric age. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 129B, 85\u201393 (2004).","journal-title":"Am. J. Med. Genet. B. Neuropsychiatr. Genet."},{"key":"23938_CR3","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1212\/01.wnl.0000343049.00540.c8","volume":"72","author":"R Schiffmann","year":"2009","unstructured":"Schiffmann, R. & Van Der Knaap, M. S. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 72, 750\u2013759 (2009).","journal-title":"Neurology"},{"key":"23938_CR4","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/S0887-8994(00)00232-0","volume":"24","author":"EM Kaye","year":"2001","unstructured":"Kaye, E. M. Update on genetic disorders affecting white matter. Pediatr. Neurol. 24, 11\u201324 (2001).","journal-title":"Pediatr. Neurol."},{"key":"23938_CR5","doi-asserted-by":"publisher","DOI":"10.1038\/srep35936","volume":"6","author":"X Wang","year":"2016","unstructured":"Wang, X. et al. The use of targeted genomic capture and massively parallel sequencing in diagnosis of Chinese leukoencephalopathies. Sci. Rep. 6, 35936 (2016).","journal-title":"Sci. Rep."},{"key":"23938_CR6","unstructured":"Summers, B. A., Cummings, J. F. & de Lahunta, A. Hereditary, familial, and idiopathic degenerative diseases in Veterinary Neuropathology 281\u2013300 (Mosby, 1995)."},{"key":"23938_CR7","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.tvjl.2004.08.015","volume":"171","author":"S Sis\u00f3","year":"2006","unstructured":"Sis\u00f3, S. et al. Neurodegenerative diseases in domestic animals: a comparative review. Vet. J. 171, 20\u201338 (2006).","journal-title":"Vet. J."},{"key":"23938_CR8","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1097\/00005072-197707000-00008","volume":"36","author":"DR Averill","year":"1977","unstructured":"Averill, D. R. & Bronson, R. T. Inherited necrotizing myelopathy of Afghan hounds. J. Neuropathol. Exp. Neurol. 36, 734\u2013747 (1977).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"23938_CR9","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1177\/030098588402100302","volume":"21","author":"DA Gamble","year":"1984","unstructured":"Gamble, D. A. & Chrisman, C. L. A leukoencephalomyelopathy of rottweiler dogs. Vet. Pathol. 21, 274\u2013280 (1984).","journal-title":"Vet. Pathol."},{"key":"23938_CR10","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.2460\/javma.1992.201.08.1222","volume":"201","author":"F Baum 3rd","year":"1992","unstructured":"Baum, F. 3rd, de Lahunta, A. & Trotter, E. J. Cervical fibrotic stenosis in a young Rottweiler. J. Am. Vet. Med. Assoc. 201, 1222\u20131224 (1992).","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"23938_CR11","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/1746-6148-9-57","volume":"9","author":"K Hirschvogel","year":"2013","unstructured":"Hirschvogel, K. et al. Magnetic resonance imaging and genetic investigation of a case of Rottweiler leukoencephalomyelopathy. BMC Vet. Res. 9, 57 (2013).","journal-title":"BMC Vet. Res."},{"key":"23938_CR12","doi-asserted-by":"publisher","first-page":"255","DOI":"10.5326\/JAAHA-MS-5864","volume":"49","author":"JS Eagleson","year":"2013","unstructured":"Eagleson, J. S., Kent, M., Platt, S. R., Rech, R. R. & Howerth, E. W. MRI findings in a rottweiler with leukoencephalomyelopathy. J. Am. Anim. Hosp. Assoc. 49, 255\u2013261 (2013).","journal-title":"J. Am. Anim. Hosp. Assoc."},{"key":"23938_CR13","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1111\/j.1939-1676.2008.0068.x","volume":"22","author":"A Oevermann","year":"2008","unstructured":"Oevermann, A., Bley, T., Konar, M., Lang, J. & Vandevelde, M. A novel leukoencephalomyelopathy of leonberger dogs. J. Vet. Intern. Med. 22, 467\u2013471 (2008).","journal-title":"J. Vet. Intern. Med."},{"key":"23938_CR14","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/0034-5288(93)90020-G","volume":"54","author":"PJJ Mandigers","year":"1993","unstructured":"Mandigers, P. J. J., van Nes, J. J., Knol, B. W., Ubbink, G. J. & Gruys, E. Hereditary necrotising myelopathy in Kooiker dogs. Res. Vet. Sci. 54, 118\u2013123 (1993).","journal-title":"Res. Vet. Sci."},{"key":"23938_CR15","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1002\/mus.10350","volume":"27","author":"GD Shelton","year":"2003","unstructured":"Shelton, G. D. et al. Inherited polyneuropathy in Leonberger dogs: a mixed or intermediate form of Charcot-Marie-Tooth disease? Muscle Nerve. 27, 471\u2013477 (2003).","journal-title":"Muscle Nerve."},{"key":"23938_CR16","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1016\/j.biopsych.2015.07.028","volume":"79","author":"HC Lu","year":"2016","unstructured":"Lu, H. C. & MacKie, K. An introduction to the endogenous cannabinoid system. Biol. Psychiatry 79, 516\u2013525 (2016).","journal-title":"Biol. Psychiatry"},{"key":"23938_CR17","doi-asserted-by":"crossref","unstructured":"Cassano, T. et al. Cannabinoid receptor 2 signaling in neurodegenerative disorders: From pathogenesis to a promising therapeutic target. Front. Neurosci. 11 (2017).","DOI":"10.3389\/fnins.2017.00030"},{"key":"23938_CR18","doi-asserted-by":"publisher","first-page":"5298","DOI":"10.1074\/jbc.M306642200","volume":"279","author":"Y Okamoto","year":"2004","unstructured":"Okamoto, Y., Morishita, J., Tsuboi, K., Tonai, T. & Ueda, N. Molecular characterization of a phospholipase D generating anandamide and its congeners. J. Biol. Chem. 279, 5298\u20135305 (2004).","journal-title":"J. Biol. Chem."},{"key":"23938_CR19","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1016\/j.bbalip.2017.08.006","volume":"1862","author":"Z Hussain","year":"2017","unstructured":"Hussain, Z., Uyama, T., Tsuboi, K. & Ueda, N. Mammalian enzymes responsible for the biosynthesis of N -acylethanolamines. Biochim. Biophys. Acta - Mol. Cell Biol. Lipids. 1862, 1546\u20131561 (2017).","journal-title":"Biochim. Biophys. Acta - Mol. Cell Biol. Lipids."},{"key":"23938_CR20","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1016\/j.tibs.2015.12.007","volume":"41","author":"I Pettinati","year":"2016","unstructured":"Pettinati, I., Brem, J., Lee, S. Y., McHugh, P. J. & Schofield, C. J. The chemical biology of human metallo-\u03b2-lactamase fold proteins. Trends Biochem. Sci. 41, 338\u2013355 (2016).","journal-title":"Trends Biochem. Sci."},{"key":"23938_CR21","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1002\/cbdv.200790155","volume":"4","author":"Y Okamoto","year":"2007","unstructured":"Okamoto, Y., Wang, J., Morishita, J. & Ueda, N. Biosynthetic pathways of the endocannabinoid anandamide. Chem. Biodivers. 4, 1842\u20131857 (2007).","journal-title":"Chem. Biodivers."},{"key":"23938_CR22","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1016\/j.str.2014.12.018","volume":"23","author":"P Magotti","year":"2015","unstructured":"Magotti, P. et al. Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids. Structure 23, 598\u2013604 (2015).","journal-title":"Structure"},{"key":"23938_CR23","doi-asserted-by":"publisher","first-page":"2908","DOI":"10.1021\/acschembio.6b00624","volume":"11","author":"E Margheritis","year":"2016","unstructured":"Margheritis, E. et al. Bile acid recognition by NAPE-PLD. ACS Chem. Biol. 11, 2908\u20132914 (2016).","journal-title":"ACS Chem. Biol."},{"key":"23938_CR24","doi-asserted-by":"publisher","first-page":"4720","DOI":"10.1021\/bi060163l","volume":"45","author":"D Leung","year":"2006","unstructured":"Leung, D., Saghatelian, A., Simon, G. M. & Cravatt, B. F. Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids. Biochemistry 45, 4720\u20134726 (2006).","journal-title":"Biochemistry"},{"key":"23938_CR25","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1039\/c000237b","volume":"6","author":"GM Simon","year":"2010","unstructured":"Simon, G. M. & Cravatt, B. F. Characterization of mice lacking candidate N-acyl ethanolamine biosynthetic enzymes provides evidence for multiple pathways that contribute to endocannabinoid production in vivo. Mol. Biosyst. 6, 1411\u20131418 (2010).","journal-title":"Mol. Biosyst."},{"key":"23938_CR26","doi-asserted-by":"publisher","first-page":"1548","DOI":"10.1111\/j.1460-9568.2007.05782.x","volume":"26","author":"A Ar\u00e9valo-Mart\u00edn","year":"2007","unstructured":"Ar\u00e9valo-Mart\u00edn, A. et al. Cannabinoids modulate Olig2 and polysialylated neural cell adhesion molecule expression in the subventricular zone of post-natal rats through cannabinoid receptor 1 and cannabinoid receptor 2. Eur. J. Neurosci. 26, 1548\u20131559 (2007).","journal-title":"Eur. J. Neurosci."},{"key":"23938_CR27","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1038\/nrn3846","volume":"15","author":"M Maccarrone","year":"2014","unstructured":"Maccarrone, M., Guzm\u00e1n, M., Mackie, K., Doherty, P. & Harkany, T. Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies. Nat. Rev. Neurosci. 15, 786\u2013801 (2014).","journal-title":"Nat. Rev. Neurosci."},{"key":"23938_CR28","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1242\/dmm.028373","volume":"10","author":"M Fern\u00e1ndez-Trapero","year":"2017","unstructured":"Fern\u00e1ndez-Trapero, M. et al. Upregulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis. Dis. Model. Mech. 10, 551\u2013558 (2017).","journal-title":"Dis. Model. Mech."},{"key":"23938_CR29","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1515\/bmc-2014-0015","volume":"5","author":"T Tanaka","year":"2014","unstructured":"Tanaka, T. & Yoshida, S. Mechanisms of remyelination: recent insight from experimental models. Biomol. Concepts. 5, 289\u2013298 (2014).","journal-title":"Biomol. Concepts."},{"key":"23938_CR30","doi-asserted-by":"publisher","first-page":"e1005848","DOI":"10.1371\/journal.pgen.1005848","volume":"12","author":"J Zhang","year":"2016","unstructured":"Zhang, J. et al. A founder mutation in VPS11 causes an autosomal recessive leukoencephalopathy linked to autophagic defects. PLoS Genet. 12, e1005848 (2016).","journal-title":"PLoS Genet."},{"key":"23938_CR31","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1007\/s00439-015-1617-7","volume":"135","author":"N Arai-Ichinoi","year":"2016","unstructured":"Arai-Ichinoi, N. et al. Genetic heterogeneity in 26 infants with a hypomyelinating leukodystrophy. Hum. Genet. 135, 89\u201398 (2016).","journal-title":"Hum. Genet."},{"key":"23938_CR32","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nature19057","volume":"536","author":"M Lek","year":"2016","unstructured":"Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 536, 285\u2013291 (2016).","journal-title":"Nature."},{"key":"23938_CR33","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.ajhg.2017.06.004","volume":"101","author":"JD Riordan","year":"2017","unstructured":"Riordan, J. D. & Nadeau, J. H. From peas to disease: modifier genes, network resilience, and the genetics of health. Am. J. Hum. Genet. 101, 177\u2013191 (2017).","journal-title":"Am. J. Hum. Genet."},{"key":"23938_CR34","doi-asserted-by":"publisher","first-page":"E3091","DOI":"10.1073\/pnas.1600084113","volume":"113","author":"EL Ivansson","year":"2016","unstructured":"Ivansson, E. L. et al. Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy. Proc. Natl. Acad. Sci. USA 113, E3091\u2013E3100 (2016).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"23938_CR35","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/nbt.3514","volume":"34","author":"R Chen","year":"2016","unstructured":"Chen, R. et al. Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases. Nat. Biotechnol. 34, 531\u2013538 (2016).","journal-title":"Nat. Biotechnol."},{"key":"23938_CR36","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-017-4081-z","volume":"18","author":"D Becker","year":"2017","unstructured":"Becker, D. et al. A GJA9 frameshift variant is associated with polyneuropathy in Leonberger dogs. BMC Genomics 18, 662 (2017).","journal-title":"BMC Genomics"},{"key":"23938_CR37","doi-asserted-by":"publisher","first-page":"e1004635","DOI":"10.1371\/journal.pgen.1004635","volume":"10","author":"KJ Ekenstedt","year":"2014","unstructured":"Ekenstedt, K. J. et al. An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs. PLoS Genet. 10, e1004635 (2014).","journal-title":"PLoS Genet."},{"key":"23938_CR38","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.celrep.2017.03.079","volume":"19","author":"HG Parker","year":"2017","unstructured":"Parker, H. G. et al. Genomic analyses reveal the influence of geographic origin, migration, and hybridization on modern dog breed development. Cell Rep. 19, 697\u2013708 (2017).","journal-title":"Cell Rep."},{"key":"23938_CR39","doi-asserted-by":"publisher","first-page":"e11258","DOI":"10.1371\/journal.pone.0011258","volume":"5","author":"C Dr\u00f6gem\u00fcller","year":"2010","unstructured":"Dr\u00f6gem\u00fcller, C. et al. A deletion in the N-Myc downstream regulated gene 1 (NDRG1) gene in Greyhounds with polyneuropathy. PLoS ONE 5, e11258 (2010).","journal-title":"PLoS ONE"},{"key":"23938_CR40","doi-asserted-by":"publisher","first-page":"e54547","DOI":"10.1371\/journal.pone.0054547","volume":"8","author":"C Bruun","year":"2013","unstructured":"Bruun, C. et al. A Gly98Val mutation in the N-Myc downstream regulated gene 1 (NDRG1) in Alaskan malamutes with polyneuropathy. PLoS ONE 8, e54547 (2013).","journal-title":"PLoS ONE"},{"key":"23938_CR41","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1093\/bioinformatics\/btm108","volume":"23","author":"YS Aulchenko","year":"2007","unstructured":"Aulchenko, Y. S., Ripke, S., Isaacs, A. & van Duijn, C. M. GenABEL: An R library for genome-wide association analysis. Bioinformatics 23, 1294\u20131296 (2007).","journal-title":"Bioinformatics"},{"key":"23938_CR42","doi-asserted-by":"crossref","first-page":"20","DOI":"10.32614\/RJ-2010-009","volume":"2","author":"L Ronnegard","year":"2010","unstructured":"Ronnegard, L., Shen, X. & Alam, M. hglm: A package for fitting hierarchical generalized linear models. R J. 2, 20\u201328 (2010).","journal-title":"R J."},{"key":"23938_CR43","doi-asserted-by":"publisher","first-page":"e1002316","DOI":"10.1371\/journal.pgen.1002316","volume":"7","author":"A Vaysse","year":"2011","unstructured":"Vaysse, A. et al. Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping. PLoS Genet. 7, e1002316 (2011).","journal-title":"PLoS Genet."},{"key":"23938_CR44","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2013-14-12-r132","volume":"14","author":"E Karlsson","year":"2013","unstructured":"Karlsson, E. et al. Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A\/B. Genome Biol. 14, R132 (2013).","journal-title":"Genome Biol."},{"key":"23938_CR45","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1086\/502802","volume":"78","author":"P Scheet","year":"2006","unstructured":"Scheet, P. & Stephens, M. A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am. J. Hum. Genet. 78, 629\u2013644 (2006).","journal-title":"Am. J. Hum. Genet."},{"key":"23938_CR46","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1093\/bib\/bbs017","volume":"14","author":"H Thorvaldsd\u00f3ttir","year":"2013","unstructured":"Thorvaldsd\u00f3ttir, H., Robinson, J. T. & Mesirov, J. P. Integrative genomics viewer (IGV): High-performance genomics data visualization and exploration. Brief. Bioinform. 14, 178\u2013192 (2013).","journal-title":"Brief. Bioinform."},{"key":"23938_CR47","doi-asserted-by":"publisher","first-page":"D777","DOI":"10.1093\/nar\/gku1174","volume":"43","author":"B Bai","year":"2015","unstructured":"Bai, B. et al. DoGSD: the dog and wolf genome SNP database. Nucleic Acids Res. 43, D777\u2013D783 (2015).","journal-title":"Nucleic Acids Res."},{"key":"23938_CR48","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nmeth0410-248","volume":"7","author":"I Adzhubei","year":"2010","unstructured":"Adzhubei, I. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248\u2013249 (2010).","journal-title":"Nat. Methods"},{"key":"23938_CR49","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1038\/nprot.2009.86","volume":"4","author":"P Kumar","year":"2009","unstructured":"Kumar, P., Henikoff, S. & Ng, P. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073\u20131081 (2009).","journal-title":"Nat. Protoc."},{"key":"23938_CR50","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/nmeth.2890","volume":"11","author":"J Schwarz","year":"2014","unstructured":"Schwarz, J., Cooper, D., Schuelke, M. & Seelow, D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat. Methods 11, 361\u2013362 (2014).","journal-title":"Nat. Methods"},{"key":"23938_CR51","doi-asserted-by":"crossref","unstructured":"Pejaver, V. et al. MutPred2: inferring the molecular and phenotypic impact of amino acid variants. bioRxiv 134981 (2017).","DOI":"10.1101\/134981"},{"key":"23938_CR52","doi-asserted-by":"publisher","first-page":"2949","DOI":"10.1534\/g3.116.033225","volume":"6","author":"DP Waluk","year":"2016","unstructured":"Waluk, D. P. et al. A splice defect in the EDA gene in dogs with an X-linked hypohidrotic ectodermal dysplasia (XLHED) phenotype. G3 (Bethesda) 6, 2949\u20132954 (2016).","journal-title":"G3 (Bethesda)"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-23938-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-23938-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-23938-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T18:34:22Z","timestamp":1720204462000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-23938-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,11]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["23938"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-23938-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,11]]},"assertion":[{"value":"6 November 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 March 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 April 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Both the University of Minnesota and the University of Bern offer a genotyping test for LEMP, as well as several other genetic conditions in dogs, in their respective laboratories. None of the authors gain financially from the proceeds of these tests, which all go to support ongoing canine genetic research. Non-financial competing interests of authors from both Universities include informal advisory relationships concerning use and interpretation of genetic testing, as well as financial support for the research, from non-profit organizations that include the Leonberger Health Foundation (USA), the International Leonberger Union, and the Swiss and German Leonberger Clubs.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"5818"}}