Relationship of neurologic degeneration to genotype in three xeroderma pigmentosum group G patients
Relationship of neurologic degeneration to genotype in three xeroderma pigmentosum group G patients
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DOI：
10.1046/j.1523-1747.2002.01782.x
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发表时间：
2002-06-01
影响因子：
6.5
通讯作者：
Kraemer, KH
中科院分区：
文献类型：
--
作者：
Emmert, S;Slor, H;Kraemer, KH
我们研究了三名新诊断的色素性干皮病互补组 G 患者，其临床特征明显不同。一名以色列-巴勒斯坦女孩 (XP96TA) 患有严重异常，提示患有色素性干皮病/科凯恩综合征，包括阳光敏感性、神经系统和发育障碍，并在 6 岁时死亡。一名白人女孩 (XP82DC) 也患有严重的阳光敏感性，并伴有神经和发育障碍，并于 5.8 岁时死亡。相比之下，一名轻度受影响的 14 岁白人女性 (XP65BE) 对阳光敏感，但没有神经系统异常。 XP96TA、XP82DC 和 XP65BE 成纤维细胞显示紫外线后细胞存活和 DNA 修复显着降低，但 XP65BE 中的这些值高于 XP82DC。 XP96TA 成纤维细胞的 XPG mRNA 表达水平非常低，而 XP65BE 成纤维细胞的 XPG mRNA 表达水平几乎正常。经紫外线处理的报告基因的宿主细胞重新激活将所有三种成纤维细胞菌株分配到罕见的着色性干皮病互补组 G（之前仅报道过其他 10 名患者）。 XP96TA 和 XP82DC 细胞的两个 XPG 等位基因均发生突变，预计会导致蛋白质严重截短，包括终止密码子和两个碱基移码。轻度 XP65BE 患者的父系等位基因存在早期终止密码子突变。 XP65BE 母体等位基因具有单碱基错义突变（G2817A、Ala874Thr），显示出补充着色性干皮病互补组 G 细胞的残余能力。这些观察结果与早期的研究一致，表明 XPG 突变（预计会导致两个等位基因中的蛋白质严重截短）与严重的色素性干皮病/科凯恩综合征神经系统症状相关。保留一个等位基因的残余功能活性与无神经系统异常的轻度临床特征相关。
We studied three newly diagnosed xeroderma pigmentosum complementation group G patients with markedy different clinical features. An Israeli-Palestinian girl (XP96TA) had severe abnormal ities suggestive of the xeroderma pigmentosum/Cockayne syndrome complex including sun sensitivity, neurologic and developmental impairment, and death by age 6 y. A Caucasian girl (XP82DC) also had severe sun sensitivity with neurologic and developmental impairment and died at 5.8 y. In contrast, a mildly affected 14-y-old Caucasian female (XP65BE) had sun sensitivity but no neurologic abnormalities. XP96TA, XP82DC, and XP65BE fibroblasts showed marked reductions in post-ultraviolet cell survival and DNA repair but these were higher in XP65BE than in XP82DC. XP96TA fibroblasts had very low XPG mRNA expression levels whereas XP65BE fibroblasts had nearly normal levels. Host cell reactivation of an ultraviolet-treated reporter assigned all three fibroblast strains to the rare xeroderma pigmentosum complementation group G (only 10 other patients previously reported). XP96TA and XP82DC cells had mutations in both XPG alleles that are predicted to result in severely truncated proteins including stop codons and two base frameshifts. The mild XP65BE patient had an early stop codon mutation in the paternal allele. The XP65BE maternal allele had a single base missense mutation (G2817A, Ala874Thr) that showed residual ability to complement xeroderma pigmentosum complementation group G cells. These observations agree with earlier studies demonstrating that XPG mutations, which are predicted to lead to severely truncated proteins in both alleles, were associated with severe xeroderma pigmentosum/Cockayne syndrome neurologic symptoms. Retaining residual functional activity in one allele was associated with mild clinical features without neurologic abnormalities.