and 3 The Jackson Laboratory, Bar Harbor, ME Pseudoxanthoma elasticum (PXE) is characterized by systemic connective tissue mineralization caused by loss-of-function mutations in the ABCC6 gene. The currently available Abcc6 -/mice represent a useful model system to study PXE pathophysiology and to explore potential treatment modalities. Abcc6 -/rats would, however, provide a more suitable model for metabolic studies and specifically unravel the role of PPi and Pi homeostasis in PXE. We have therefore generated Abcc6 -/rats using zinc finger nuclease (ZFN), targeting the first coding exon of Abcc6. Five germline transmission competent rats were identified that harbored deletions ranging from 10 to 23 bp surrounding the ZFN target site. These mutations were predicted to cause out-of-frame translation and induce a premature stop codon. Immunostaining of liver sections using a rat ABCC6 specific antibody showed plasma membrane expression in basolateral surface of hepatocytes in wild type rats and complete absence in the homozygous mutant rats. As a consequence of ABCC6 deficiency, complete necropsy of three mutant lines demonstrated ectopic mineralization in the muzzle skin, eyes, and arterial blood vessels in the knockout rats, features mimicking human PXE. Mineralization in the dermal sheath of vibrissae was also monitored by small animal CT scanning, which allows noninvasive evaluation of the mineralization process. Similar to human PXE patients, clinical chemistry did not reveal differences in serum calcium and phosphorus levels between wild type and Abcc6 -/rats. However, plasma PPi level was significantly reduced (<60%) in the Abcc6 -/rats as compared to wild type rats, leading to a significantly lower PPi/Pi ratio. Since PPi is physiologically a potent antimineralization factor, the results highlight the role of PPi in the context of the PPi/Pi ratio in the novel Abcc6 -/rat model due to loss-of-function of ABCC6, leading to ectopic mineralization in PXE.
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