Functional Assessment of Missense Variants in the ABCC6 Gene Implicated in Pseudoxanthoma Elasticum, a Heritable Ectopic Mineralization Disorder.
Functional Assessment of Missense Variants in the ABCC6 Gene Implicated in Pseudoxanthoma Elasticum, a Heritable Ectopic Mineralization Disorder.
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与弹性假黄瘤（一种遗传性异位矿化障碍）有关的 ABCC6 基因错义变异体的功能评估。
DOI：
10.1016/j.jid.2021.08.435
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Kowal L;Huang J;Luo H;Singh J;Snook AE;Uitto J;Li Q
弹性假黄瘤（PXE）是一种遗传性多系统异位矿化疾病，由ABCC6基因失活突变引起。编码的蛋白ABCC6是一种跨膜转运蛋白，通过影响血浆中PPi（软结缔组织矿化的有效抑制剂）的水平，在肝细胞中具有特殊的外排功能。血浆PPi水平降低是PXE异位矿化的基础。在这项研究中，我们利用腺病毒介导的肝脏特异性ABCC6转基因表达系统，在PXE ABCC6 - / -小鼠模型中表征了三种人类ABCC6错义变体的致病性。变异p.L420V和p.R1064W被发现是良性的，因为它们在肝细胞中的丰度和质膜定位与野生型人ABCC6转基因相似，使血浆PPi水平正常化，并阻止枪口皮肤触毛真皮鞘矿化，这是ABCC6 - / -小鼠的表型标志。相比之下，p.S400F被证明是致病的，因为它不能使血浆PPi水平正常化，尽管在肝细胞中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在ABCC6 - / -小鼠肝脏中的表达可以提供一个模型系统，有效地阐明PXE患者中发现的人类ABCC6错义变异的多方面功能后果。
Pseudoxanthoma elasticum (PXE), a heritable multi-system 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 PPi, a potent inhibitor of mineralization in soft connective tissues. Reduced plasma PPi levels underlie the ectopic mineralization in PXE. 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 PXE. Variants p.L420V and p.R1064W were found benign as they had abundance and plasma membrane localization in hepatocytes similar to the wild-type human ABCC6 transgene, normalized plasma PPi 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 as it failed to normalize plasma PPi levels and had no effect on ectopic mineralization despite normal expression and proper localization in hepatocytes. These results demonstrated 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 PXE.
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DOI：
10.1073/pnas.1319582110
发表时间：
2013-12-10
影响因子：
11.1
作者：
Jansen, Robert S.;Kucukosmanoglu, Asli;van de Wetering, Koen
通讯作者：
van de Wetering, Koen
影响因子：
6.5
作者：
Pomozi, Viola;Brampton, Christopher;Fueloep, Krisztina;Chen, Li-Hsieh;Apana, Ailea;Li, Qiaoli;Uitto, Jouni;Le Saux, Olivier;Varadi, Andras
通讯作者：
Varadi, Andras
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
64.8
作者：
FLEISCH, H;RUSSEL, RGG;STRAUMANN, F
通讯作者：
STRAUMANN, F
影响因子：
3.6
作者：
Li Q;Jiang Q;Pfendner E;Váradi A;Uitto J
通讯作者：
Uitto J