Mutated Pkhd1 alone is sufficient to cause autoimmune biliary disease on the nonobese diabetic (NOD) genetic background

AbstractWe previously reported that nonobese diabetic (NOD) congenic mice (NOD.c3c4 mice) developed an autoimmune biliary disease (ABD) with similarities to human primary biliary cholangitis (PBC), including anti-mitochondrial antibodies and organ-specific biliary lymphocytic infiltrates. We narrowed the possible contributory regions in a novel NOD.Abd3 congenic mouse to a B10 congenic region on chromosome 1 ( “Abd3”) and a mutatedPkhd1 gene (Pkhd1del36 −67) upstream fromAbd3, and we showed via backcrossing studies that the NOD genetic background was necessary for disease. Here, we show that NOD.Abd3 mice develop anti-PDC-E2 autoantibodies at high levels, and that placing the chromosome 1 interval onto ascid 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 theAbd3 locus were necessary and sufficient for disease. Here, using a classic recombinant breeding approach, we prove that the mutatedPkhd1del36 −67 alone, on the NOD background, causes ABD. Further characterization of the mutant sequence demonstrated that thePkhd1 gene is disrupted by an ETnII-beta retrotransposon inserted in intron 35 in an anti-sense orientation. HomozygousPkhd1 mutations significantly affect viability, with the offspring skewed away from a Mendelian distribution towards NODPkhd1 homozygous or heterozygous genotypes. Cell-specifi...
Source: Immunogenetics - Category: Genetics & Stem Cells Source Type: research