A common duplication in the lysyl hydroxylase gene of patients with Ehlers Danlos syndrome type VI results in preferential stimulation of lysyl hydroxylase activity and mRNA by hydralazine.
A common duplication in the lysyl hydroxylase gene of patients with Ehlers Danlos syndrome type VI results in preferential stimulation of lysyl hydroxylase activity and mRNA by hydralazine.
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VI 型 Ehlers Danlos 综合征患者的赖氨酰羟化酶基因中常见的重复导致肼苯哒嗪优先刺激赖氨酰羟化酶活性和 mRNA。
DOI：
10.1006/abbi.1997.0319
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Pinnell,SR
中科院分区：
文献类型：
--
作者：
Yeowell,HN;Walker,LC;Murad,S;Pinnell,SR
VI 型埃勒斯丹洛斯综合征 (EDS VI) 患者的生化特征是缺乏赖氨酰羟化酶 (LH)，这种酶可将胶原蛋白生物合成中形成稳定交联所需的赖氨酸残基羟化。最近，在 35 个 EDS VI 家族中的 19% 中，LH 基因中七个外显子的重复已被确定为 EDS VI 的常见原因。我们观察到，在具有这种重复突变的患者的成纤维细胞中，给予肼屈嗪（一种铁螯合剂）和抗坏血酸（LH 活性的辅助因子），对 LH 活性及其 mRNA 的刺激作用显着高于其他不具有这种重复突变的 EDS VI 患者。将这些试剂单独或组合给予来自 5 名重复纯合患者的成纤维细胞，在 72 小时时刺激 LH 活性基础水平较低（<正常值的 20%）五至六倍（肼屈嗪 ± 抗坏血酸）和两倍（单独抗坏血酸）。这与在四名患者的经类似处理的成纤维细胞中测量到的 LH mRNA 稳态水平的增加是一致的。相比之下，肼苯哒嗪±抗坏血酸仅使其他 6 名 EDS VI 患者的成纤维细胞中的 LH 活性以及其中 4 名没有重复的患者的 mRNA 增加了三到四倍。在携带重复的 EDS VI 细胞中肼苯哒嗪优先刺激 LH 活性和 mRNA 的机制尚不清楚，但这可能归因于例如 LH 基因重复区域内存在增强子序列。
Patients with Ehlers Danlos Syndrome type VI (EDS VI) are biochemically characterized by a deficiency of lysyl hydroxylase (LH), an enzyme that hydroxylates lysine residues required in the formation of stable crosslinks in collagen biosynthesis. Recently, in 19% of 35 EDS VI families, a duplication of seven exons in the LH gene has been identified as a common cause of EDS VI. We have observed that in fibroblasts from patients with this duplication mutation, administration of hydralazine, an iron-chelating agent, and ascorbate, a cofactor for LH activity, stimulates LH activity and its mRNA significantly more than in other EDS VI patients who do not have this duplication. Administration of these reagents, either singly or in combination, to fibroblasts from five patients homozygous for the duplication stimulated the low basal level of LH activity (<20% of normal) by five- to sixfold (hydralazine ± ascorbate) and by twofold (ascorbate alone) at 72 h. This paralleled the increase in the steady-state level of mRNA for LH measured in similarly treated fibroblasts from four of these patients. In contrast, the activity of LH in fibroblasts from six other EDS VI patients and the mRNA from four of these patients who did not have the duplication were increased only three- to fourfold by hydralazine ± ascorbate. The mechanism for the preferential stimulation of LH activity and mRNA by hydralazine in the EDS VI cells carrying the duplication is unknown, but it could be attributed to the presence of, for example, an enhancer sequence within the duplicated region of the LH gene.