Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, 233 South 10th Street, Suite 450 BLSB, Philadelphia, PA, 19107, USA.
J Mol Med (Berl). 2010 Feb;88(2):173-81. doi: 10.1007/s00109-009-0522-8. Epub 2009 Sep 27.
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 gamma-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 five 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 approximately 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 and 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 approximately 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.
弹性假黄瘤（PXE）是一种常染色体隐性疾病，其特征为结缔组织异位矿化，并表现出相当大的个体间和家族内表型变异性。PXE 是由 ABCC6 基因突变引起的，而在小鼠中靶向敲除 Abcc6 可重现 PXE。在这项研究中，我们检验了这样一个假设，即编码 γ-谷氨酰羧化酶的 GGCX 基因可能会干扰 Abcc6（-/-）小鼠的矿化过程。因此，分别在 129S1;C57 和 129S1;129X1;C57 遗传背景上生成 Abcc6（-/-）和 Ggcx（+/-）小鼠，并将它们与 C57BL/6J 进行了五代回交。因此，这些品系的差异在于 129X1 对小鼠背景的贡献。然后，我们通过杂交 Abcc6（-/-）和 Ggcx（+/-）小鼠，生成了 Abcc6（-/-）;Ggcx（+/+）和 Abcc6（-/-）;Ggcx（+/-）小鼠。通过计算机形态计量分析评估了触须结缔组织囊的矿化程度，这是 PXE 矿化过程的生物标志物，并通过组织中的钙和磷酸盐水平进行了比色定量。与野生型小鼠相比，Abcc6（-/-）小鼠的触须矿化大约在 5-6 周龄时发生，并在 3 月龄时显著增强（超过 10 倍，p <0.001）。然而，Abcc6（-/-）;Ggcx（+/+）小鼠的矿化起始时间延迟至 3 至 4 月龄，表明遗传背景在修饰矿化过程中发挥了作用。与年龄匹配的 Abcc6（-/-）;Ggcx（+/+）小鼠相比，Abcc6（-/-）;Ggcx（+/-）小鼠的矿化速度加快，在 3、4 和 9 月龄时差异约为 3 倍（p <0.01）。在这些小鼠中，通过特殊定制的饮食也可以加速矿化过程，该饮食具有矿物质修饰。这些发现表明，GGCX 基因和遗传背景以及饮食因素在调节由 ABCC6 功能丧失突变引起的 PXE 的表型严重程度方面都发挥了作用。
