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We narrowed the possible contributory regions in a novel NOD.<jats:italic>Abd3<\/jats:italic> congenic mouse to a B10 congenic region on chromosome 1 (\u201c<jats:italic>Abd3<\/jats:italic>\u201d) and a mutated <jats:italic>Pkhd1<\/jats:italic> gene (<jats:italic>Pkhd1<\/jats:italic><jats:sup>del36\u221267<\/jats:sup>) upstream from <jats:italic>Abd3<\/jats:italic>, and we showed via backcrossing studies that the NOD genetic background was necessary for disease. Here, we show that NOD.<jats:italic>Abd3<\/jats:italic> mice develop anti-PDC-E2 autoantibodies at high levels, and that placing the chromosome 1 interval onto a <jats:italic>scid<\/jats:italic> background eliminates disease, demonstrating the critical role of the adaptive immune system in pathogenesis. While the NOD genetic background is essential for disease, it was still unclear which of the two regions in the <jats:italic>Abd3<\/jats:italic> locus were necessary and sufficient for disease. Here, using a classic recombinant breeding approach, we prove that the mutated <jats:italic>Pkhd1<\/jats:italic><jats:sup>del36\u221267<\/jats:sup> alone, on the NOD background, causes ABD. Further characterization of the mutant sequence demonstrated that the <jats:italic>Pkhd1<\/jats:italic> gene is disrupted by an ETnII-beta retrotransposon inserted in intron 35 in an anti-sense orientation. Homozygous <jats:italic>Pkhd1<\/jats:italic> mutations significantly affect viability, with the offspring skewed away from a Mendelian distribution towards NOD <jats:italic>Pkhd1<\/jats:italic> homozygous or heterozygous genotypes. Cell-specific abnormalities, on a susceptible genetic background, can therefore induce an organ-specific autoimmunity directed to the affected cells. Future work will aim to characterize how mutant <jats:italic>Pkhd1<\/jats:italic> can cause such an autoimmune response.<\/jats:p>","DOI":"10.1007\/s00251-022-01276-3","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T02:02:27Z","timestamp":1663034547000},"page":"27-37","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mutated Pkhd1 alone is sufficient to cause autoimmune biliary disease on the nonobese diabetic (NOD) genetic background"],"prefix":"10.1007","volume":"75","author":[{"given":"David E.","family":"Adams","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke S.","family":"Heuer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Rojas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weici","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M.","family":"Ridgway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,9,13]]},"reference":[{"key":"1276_CR1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.874769","author":"A-M Aubin","year":"2022","unstructured":"Aubin A-M, Lombard-Vadnais F, Collin R, Aliesky HA, McLachlan SM, Lesage S (2022) The NOD mouse beyond autoimmune diabetes. 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