{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T18:47:32Z","timestamp":1740163652110,"version":"3.37.3"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,2,21]],"date-time":"2020-02-21T00:00:00Z","timestamp":1582243200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,2,21]],"date-time":"2020-02-21T00:00:00Z","timestamp":1582243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100013927","name":"National MPS Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013927","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001458","name":"American Kennel Club Canine Health Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001458","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RR002512 and OD010939","RR002512 and OD010939","RR002512 and OD010939"],"award-info":[{"award-number":["RR002512 and OD010939","RR002512 and OD010939","RR002512 and OD010939"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mucopolysaccharidosis (MPS) IIIB (Sanfilippo syndrome B; OMIM 252920), is a lysosomal storage disease with progressive neurological signs caused by deficient activity of alpha-N-acetylglucosaminidase (NAGLU, EC 3.2.1.50). Herein we report the causative variant in the <jats:italic>NAGLU<\/jats:italic> gene in Schipperke dogs and a genotyping survey in the breed. All six exons and adjacent regions of the <jats:italic>NAGLU<\/jats:italic> gene were sequenced from six healthy appearing and three affected Schipperkes. DNA fragment length and TaqMan assays were used to genotype privately owned Schipperkes. A single variant was found in exon 6 of MPS IIIB affected Schipperkes: an insertion consisting of a 40\u201370\u2009bp poly-A and an 11\u2009bp duplication of the exonic region preceding the poly-A (XM_548088.6:c.2110_2111ins[A(40_70);2100_2110]) is predicted to insert a stretch of 13 or more lysines followed by either an in-frame insertion of a repeat of the four amino acids preceding the lysines, or a frameshift. The clinically affected Schipperkes were homozygous for this insertion, and the sequenced healthy dogs were either heterozygous or homozygous for the wild-type allele. From 2003\u20132019, 3219 Schipperkes were genotyped. Of these, 1.5% were homozygous for this insertion and found to be clinically affected, and 23.6% were heterozygous for the insertion and were clinically healthy, the remaining 74.9% were homozygous for the wild-type and were also clinically healthy. The number of dogs homozygous and heterozygous for the insertion declined rapidly after the initial years of genotyping, documenting the benefit of a DNA screening program in a breed with a small gene pool. In conclusion, a causative <jats:italic>NAGLU<\/jats:italic> variant in Schipperke dogs with MPS IIIB was identified and was found at high frequency in the breed. Through genotyping and informed breeding practices, the prevalence of canine MPS IIIB has been drastically reduced in the Schipperke population worldwide.<\/jats:p>","DOI":"10.1038\/s41598-020-60121-3","type":"journal-article","created":{"date-parts":[[2020,2,21]],"date-time":"2020-02-21T11:03:29Z","timestamp":1582283009000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["An exonic insertion in the NAGLU gene causing Mucopolysaccharidosis IIIB in Schipperke dogs"],"prefix":"10.1038","volume":"10","author":[{"given":"Karthik","family":"Raj","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N. Matthew","family":"Ellinwood","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Urs","family":"Giger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,2,21]]},"reference":[{"key":"60121_CR1","unstructured":"Neufeld, E. F. & Muenzer, J. The Mucopolysaccharidoses in The Online Metabolic and Molecular Bases of Inherited Disease (eds Valle, D., Antonarakis, S., Ballabio, A., Beaudet, A. & Mitchell, G. A.), http:\/\/ommbid.mhmedical.com\/content.aspx?bookid=2709&sectionid=225544161. (McGraw-Hill, New York, Accessed October 25, 2019)."},{"key":"60121_CR2","doi-asserted-by":"crossref","unstructured":"Haskins, M. & Giger, U. Chapter 24 - Lysosomal Storage Diseases. Clinical Biochemistry of Domestic Animals (Sixth Edition) Sixth Edition, 731\u2013749 (2008).","DOI":"10.1016\/B978-0-12-370491-7.00024-6"},{"key":"60121_CR3","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1016\/S0888-7543(05)80182-X","volume":"14","author":"KP Menon","year":"1992","unstructured":"Menon, K. P., Tieu, P. T. & Neufeld, E. F. Architecture of the canine IDUA gene and mutation underlying canine mucopolysaccharidosis I. Genomics 14, 763\u2013768 (1992).","journal-title":"Genomics"},{"key":"60121_CR4","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1006\/geno.2000.6275","volume":"68","author":"EL Aronovich","year":"2000","unstructured":"Aronovich, E. L. et al. Canine Heparan Sulfate Sulfamidase and the Molecular Pathology Underlying Sanfilippo Syndrome Type A in Dachshunds. Genomics 68, 80\u201384 (2000).","journal-title":"Genomics"},{"key":"60121_CR5","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1006\/geno.2002.6699","volume":"79","author":"G Yogalingam","year":"2002","unstructured":"Yogalingam, G., Pollard, T., Gliddon, B., Jolly, R. D. & Hopwood, J. J. Identification of a Mutation Causing Mucopolysaccharidosis Type IIIA in New Zealand Huntaway Dogs. Genomics 79, 150\u2013153 (2002).","journal-title":"Genomics"},{"key":"60121_CR6","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1080\/00480169.2011.642791","volume":"60","author":"R Jolly","year":"2012","unstructured":"Jolly, R. et al. Mucopolysaccharidosis type VI in a Miniature Poodle-type dog caused by a deletion in the arylsulphatase B gene. New Zealand Veterinary Journal 60, 183\u2013188 (2012).","journal-title":"New Zealand Veterinary Journal"},{"key":"60121_CR7","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1177\/0300985817732115","volume":"55","author":"P Wang","year":"2018","unstructured":"Wang, P. et al. Mucopolysaccharidosis Type VI in a Great Dane Caused by a Nonsense Mutation in the ARSB Gene. Veterinary Pathology 55, 286\u2013293 (2018).","journal-title":"Veterinary Pathology"},{"key":"60121_CR8","doi-asserted-by":"publisher","first-page":"553","DOI":"10.2460\/javma.2004.224.553","volume":"224","author":"DC Silverstein Dombrowski","year":"2004","unstructured":"Silverstein Dombrowski, D. C. et al. Mucopolysaccharidosis type VII in a German Shepherd Dog. Journal of the American Veterinary Medical Association 224, 553\u2013557 (2004).","journal-title":"Journal of the American Veterinary Medical Association"},{"key":"60121_CR9","doi-asserted-by":"publisher","first-page":"e40281","DOI":"10.1371\/journal.pone.0040281","volume":"7","author":"MK Hyt\u00f6nen","year":"2012","unstructured":"Hyt\u00f6nen, M. K. et al. A Novel GUSB Mutation in Brazilian Terriers with Severe Skeletal Abnormalities Defines the Disease as Mucopolysaccharidosis VII. PloS one 7, e40281 (2012).","journal-title":"PloS one"},{"key":"60121_CR10","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1023\/A:1025177411938","volume":"26","author":"N Ellinwood","year":"2003","unstructured":"Ellinwood, N. et al. A model of mucopolysaccharidosis IIIB (Sanfilippo syndrome type IIIB): N-acetyl-\u03b1-D-glucosaminidase deficiency in Schipperke dogs. J Inherit Metab Dis 26, 489\u2013504 (2003).","journal-title":"J Inherit Metab Dis"},{"key":"60121_CR11","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1006\/geno.2001.6552","volume":"74","author":"EL Aronovich","year":"2001","unstructured":"Aronovich, E. L., Johnston, J. M., Wang, P., Giger, U. & Whitley, C. B. Molecular Basis of Mucopolysaccharidosis Type IIIB in Emu (Dromaius novaehollandiae): An Avian Model of Sanfilippo Syndrome Type B. Genomics 74, 299\u2013305 (2001).","journal-title":"Genomics"},{"key":"60121_CR12","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1007\/s10545-007-0539-5","volume":"30","author":"L Karageorgos","year":"2007","unstructured":"Karageorgos, L., Hill, B., Bawden, M. J. & Hopwood, J. J. Bovine mucopolysaccharidosis type IIIB. 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Asian-Australasian journal of animal sciences 29, 925\u2013937 (2016).","journal-title":"Asian-Australasian journal of animal sciences"},{"key":"60121_CR15","doi-asserted-by":"publisher","first-page":"bio035386","DOI":"10.1242\/bio.035386","volume":"7","author":"Q Yang","year":"2018","unstructured":"Yang, Q. et al. A model of mucopolysaccharidosis type IIIB in pigs. Biology open 7, bio035386 (2018).","journal-title":"Biology open"},{"key":"60121_CR16","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1086\/301682","volume":"62","author":"HG Zhao","year":"1998","unstructured":"Zhao, H. G., Aronovich, E. L. & Whitley, C. B. Genotype-Phenotype Correspondence in Sanfilippo Syndrome Type B. The American Journal of Human Genetics 62, 53\u201363 (1998).","journal-title":"The American Journal of Human Genetics"},{"key":"60121_CR17","first-page":"247","volume":"10","author":"E Tcherneva","year":"2007","unstructured":"Tcherneva, E. & Giger, U. Molecular base of coagulation factor XI deficiency in Kerry Blue Terrier. Bulgarian Journal of Veterinary Medicine 10, 247\u2013255 (2007).","journal-title":"Bulgarian Journal of Veterinary Medicine"},{"key":"60121_CR18","doi-asserted-by":"publisher","first-page":"527","DOI":"10.2460\/ajvr.71.5.527","volume":"71","author":"MA Bishop","year":"2010","unstructured":"Bishop, M. A., Xenoulis, P. G., Levinski, M. D., Suchodolski, J. S. & Steiner, J. M. Identification of variants of the SPINK1 gene and their association with pancreatitis in Miniature Schnauzers. American journal of veterinary research 71, 527\u2013533 (2010).","journal-title":"American journal of veterinary research"},{"key":"60121_CR19","doi-asserted-by":"publisher","first-page":"e51598","DOI":"10.1371\/journal.pone.0051598","volume":"7","author":"K Miyadera","year":"2012","unstructured":"Miyadera, K., Brierley, I., Aguirre-Hern\u00e1ndez, J., Mellersh, C. S. & Sargan, D. R. 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Disease models & mechanisms 9, 25\u201338 (2016).","journal-title":"Disease models & mechanisms"},{"key":"60121_CR24","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1006\/geno.1999.5948","volume":"61","author":"JMH Kijas","year":"1999","unstructured":"Kijas, J. M. H. et al. A Missense Mutation in the \u03b2-2 Integrin Gene (ITGB2) Causes Canine Leukocyte Adhesion Deficiency. Genomics 61, 101\u2013107 (1999).","journal-title":"Genomics"},{"key":"60121_CR25","doi-asserted-by":"publisher","first-page":"1443","DOI":"10.2460\/ajvr.2002.63.1443","volume":"63","author":"DP Bhalerao","year":"2002","unstructured":"Bhalerao, D. P., Rajpurohit, Y., Vite, C. H. & Giger, U. Detection of a genetic mutation for myotonia congenita among Miniature Schnauzers and identification of a common carrier ancestor. American journal of veterinary research 63, 1443\u20131447 (2002).","journal-title":"American journal of veterinary research"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-60121-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-60121-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-60121-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T07:26:50Z","timestamp":1670311610000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-60121-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,21]]},"references-count":25,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["60121"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-60121-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2020,2,21]]},"assertion":[{"value":"15 November 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 February 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 February 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"K.R., M.E. and U.G. are\/were members of the not-for-profit PennGen Laboratories, which offer metabolic and DNA testing for mucopolysaccharidosis and other hereditary diseases and inborn errors of metabolism.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3170"}}