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In the current study, we have performed series of clinical, pathological and genetic examinations to characterize a previously unreported skeletal disease in the Karelian Bear Dog (KBD) breed. The disease was recognized in seven KBD puppies with a variable presentation of skeletal hypomineralization, growth retardation, seizures and movement difficulties. Exome sequencing of one affected dog revealed a homozygous missense variant (c.1301T\u2009&gt;\u2009G; p.V434G) in the tissue non-specific alkaline phosphatase gene, <jats:italic>ALPL<\/jats:italic>. The identified recessive variant showed full segregation with the disease in a cohort of 509 KBDs with a carrier frequency of 0.17 and was absent from 303 dogs from control breeds. In humans, recessive and dominant <jats:italic>ALPL<\/jats:italic> mutations cause hypophosphatasia (HPP), a metabolic bone disease with highly heterogeneous clinical manifestations, ranging from lethal perinatal hypomineralization to a relatively mild dental disease. Our study reports the first naturally occurring HPP in animals, resembling the human infantile form. The canine HPP model may serve as a preclinical model while a genetic test will assist in breeding programs.<\/jats:p>","DOI":"10.1038\/s41598-018-37801-2","type":"journal-article","created":{"date-parts":[[2019,1,30]],"date-time":"2019-01-30T11:04:42Z","timestamp":1548846282000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A homozygous missense variant in the alkaline phosphatase gene ALPL is associated with a severe form of canine hypophosphatasia"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2044-2960","authenticated-orcid":false,"given":"Kaisa","family":"Ky\u00f6stil\u00e4","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pernilla","family":"Syrj\u00e4","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anu K.","family":"Lappalainen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4072-0996","authenticated-orcid":false,"given":"Meharji","family":"Arumilli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sruthi","family":"Hundi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veera","family":"Karkamo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ranno","family":"Viitmaa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marjo K.","family":"Hyt\u00f6nen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannes","family":"Lohi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,1,30]]},"reference":[{"key":"37801_CR1","doi-asserted-by":"publisher","first-page":"2869","DOI":"10.1002\/ajmg.a.37365","volume":"167A","author":"L Bonafe","year":"2015","unstructured":"Bonafe, L. et al. 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