The mineralization phenotype in Abcc6 ( -/- ) mice is affected by Ggcx gene deficiency and genetic background--a model for pseudoxanthoma elasticum.
The mineralization phenotype in Abcc6 ( -/- ) mice is affected by Ggcx gene deficiency and genetic background--a model for pseudoxanthoma elasticum.
复制标题
DOI：
10.1007/s00109-009-0522-8
复制
发表时间：
2010-02
影响因子：
4.7
通讯作者：
Uitto, Jouni
中科院分区：
文献类型：
--
作者：
Li, Qiaoli;Uitto, Jouni
弹性纤维假黄瘤（PXE）是一种常染色体隐性遗传疾病，其特征是结缔组织异位矿化，并显示出相当大的家族内和家族间表型变异。PXE是由ABCC 6基因突变引起的，在小鼠中靶向切除Abcc 6重演了PXE。在这项研究中，我们检验了编码γ-谷氨酰羧化酶的GGCX基因可能干扰Abcc 6 −/−小鼠矿化过程的假设。因此，Abcc 6 −/−和Ggcx+/−小鼠分别在129 S1;C57和129 S1; 129 X1;C57遗传背景下产生，并与C57 BL/6 J回交5代。因此，这些品系的差异在于129 X1对小鼠背景的贡献。然后，我们通过杂交Abcc 6 −/−和Ggcx+/−小鼠来产生Abcc 6 −/−; Ggcx+/+和Abcc 6 −/−; Ggcx +/−小鼠。通过计算机化形态测定分析和比色法定量测定组织中钙和磷酸盐水平，评价了触须结缔组织囊（PXE矿化过程的生物标志物）的矿化程度。Abcc 6 −/−小鼠的触须矿化发生在5-6周龄，与野生型小鼠相比，在3月龄时显著增强（>10倍，p<0.001）。然而，Abcc 6 −/−;Ggcx+/+小鼠的矿化开始延迟至3-4个月大，这表明遗传背景在改变矿化过程中起作用。与年龄匹配的Abcc 6 −/−;Ggcx+/+小鼠相比，Abcc 6 −/−;Ggcx +/−小鼠的矿化加速，在3、4和9月龄时差异约为3倍（p<0.01）。在这些小鼠中，通过特殊定制的矿物质改良饮食也加速了矿化过程。这些发现表明GGCX基因和遗传背景以及饮食因素在调节ABCC 6功能丧失突变引起的PXE表型严重程度中的作用。
Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder characterized by ectopic mineralization of connective tissues, and shows considerable intra- and inter-familial phenotypic variability. PXE is caused by mutations in the ABCC6 gene, and targeted ablation of Abcc6 in mouse recapitulates PXE. In this study, we examined the hypothesis that the GGCX gene encoding γ-glutamyl carboxylase may interfere with the mineralization process in Abcc6−/− mice. Thus, Abcc6−/− and Ggcx+/− mice were generated on 129S1;C57 and 129S1;129X1;C57 genetic backgrounds, respectively, and backcrossed with C57BL/6J for 5 generations. Thus, these strains differ by the 129X1 contribution to the background of the mice. We then generated Abcc6−/−;Ggcx+/+ and Abcc6−/−;Ggcx+/− mice by crossing Abcc6−/− and Ggcx+/− mice. The degree of mineralization of connective capsule of vibrissae, a biomarker of the mineralization process in PXE, was evaluated by computerized morphometric analysis and quantified colorimetrically by calcium and phosphate levels in tissues. The mineralization of the vibrissae in Abcc6−/− mice takes place at ~5-6 weeks of age and is significantly enhanced at 3 months of age in comparison to wild-type mice (>10-fold, p<0.001). However, the onset of mineralization in Abcc6−/−;Ggcx+/+ mice was delayed until between 3-4 months of age, suggesting that the genetic background plays a role in modifying the mineralization process. The mineralization in the Abcc6−/−;Ggcx+/− mice was accelerated in comparison with age-matched Abcc6−/−;Ggcx+/+ mice, with ~3-fold difference at 3, 4 and 9 months of age (p<0.01). The mineralization process was also accelerated in these mice by a special custom-designed diet with mineral modifications. These findings suggest a role for both the GGCX gene and the genetic background as well as dietary factors in modulating the phenotypic severity of PXE caused by loss-of-function mutations in ABCC6.
登录
查看更多内容
DOI：
10.1038/jid.2008.391
发表时间：
2009-06
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.6
作者：
LaRusso, Jennifer;Jiang, Qiujie;Uitto, Jouni
通讯作者：
Uitto, Jouni
DOI：
10.1097/00075197-200011000-00004
发表时间：
2000-11-01
影响因子：
3.1
作者：
Shearer, M J
通讯作者：
Shearer, M J
影响因子：
3.6
作者：
Li Q;Jiang Q;Pfendner E;Váradi A;Uitto J
通讯作者：
Uitto J
影响因子：
6.5
作者：
Ringpfeil, Franziska;McGuigan, Kelly;Uitto, Jouni
通讯作者：
Uitto, Jouni