Abstract：
Pseudoxanthoma elasticum, a heritable multisystem ectopic mineralization disorder, is caused by inactivating mutations in the ABCC6 gene. The encoded protein, ABCC6, a transmembrane transporter, has a specialized efflux function in hepatocytes by contributing to plasma levels of inorganic pyrophosphate, a potent inhibitor of mineralization in soft connective tissues. Reduced plasma inorganic pyrophosphate levels underlie the ectopic mineralization in pseudoxanthoma elasticum. In this study, we characterized the pathogenicity of three human ABCC6 missense variants using an adenovirus-mediated liver-specific ABCC6 transgene expression system in an Abcc6-/- mouse model of pseudoxanthoma elasticum. Variants p.L420V and p.R1064W were found benign because they had abundance and plasma membrane localization in hepatocytes similar to the wild-type human ABCC6 transgene, normalized plasma inorganic pyrophosphate levels, and prevented mineralization in the dermal sheath of vibrissae in muzzle skin, a phenotypic hallmark in the Abcc6-/- mice. In contrast, p.S400F was shown to be pathogenic because it failed to normalize plasma inorganic pyrophosphate levels and had no effect on ectopic mineralization despite its normal expression and proper localization in hepatocytes. These results showed that adenovirus-mediated hepatic ABCC6 expression in Abcc6-/- mice can provide a model system to effectively elucidate the multifaceted functional consequences of human ABCC6 missense variants identified in patients with pseudoxanthoma elasticum.
摘要：
弹性假性黄瘤，可遗传的多系统异位矿化障碍，是由ABCC6基因的失活突变引起的。编码的蛋白质，ABCC6，一种跨膜转运蛋白，通过促进无机焦磷酸盐的血浆水平，在肝细胞中具有专门的外排功能，软结缔组织中矿化的有效抑制剂。血浆无机焦磷酸盐水平降低是弹性假性黄瘤异位矿化的基础。在这项研究中,我们使用腺病毒介导的肝脏特异性ABCC6转基因表达系统在Abcc6-/-弹性假性黄瘤小鼠模型中表征了三种人ABCC6错义变体的致病性.发现变异p.L420V和p.R1064W是良性的，因为它们在肝细胞中的丰度和质膜定位类似于野生型人ABCC6转基因，归一化血浆无机焦磷酸盐水平，并防止枪口皮肤中vibrisae的真皮鞘矿化，Abcc6-/-小鼠的表型标志。相比之下,p.S400F被证明是致病性的，因为它未能使血浆无机焦磷酸盐水平正常化，并且尽管其在肝细胞中的正常表达和适当定位，但对异位矿化没有影响。这些结果表明，腺病毒介导的Abcc6-/-小鼠中的肝ABCC6表达可以提供模型系统，以有效阐明在弹性假性黄瘤患者中鉴定出的人ABCC6错义变体的多方面功能后果。
