Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect
Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect
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DOI：
10.1073/pnas.1519444113
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发表时间：
2016-03-01
影响因子：
11.1
通讯作者：
Lehmann, Alan R.
中科院分区：
文献类型：
--
作者：
Fassihi, Hiva;Sethi, Mieran;Lehmann, Alan R.
着色性干皮病（XP）是一种罕见的DNA修复疾病，其特征是对紫外线辐射（UVR）诱导的皮肤色素沉着、皮肤癌、眼表疾病的易感性增加，并且在一些患者中，晒伤和神经退行性变。在遗传学上，它被分配到八个互补组（XP-A到-G和变体）。在过去的5年中，英国国家多学科XP服务为89例XP患者提供了随访，代表了英国大部分XP患者。使用评分系统对疾病严重程度进行分类，已经测量了致病突变、DNA修复水平以及与皮肤病学、眼科学和神经病学相关的60多个临床变量。这种深层的表型分析揭示了互补组之间和互补组内的临床特征的意外异质性。皮肤癌在XP-C、XP-E和XP-V患者中最常见，先前基于细胞分析被认为是较温和的组。这些患者有正常的晒伤反应，因此诊断较晚，不太可能坚持紫外线防护。XP-C患者对眼部损伤特别敏感，XP-F和XP-G患者似乎比其他XP组更不易患皮肤癌。在XP组内，不同的突变赋予神经损伤的易感性或抵抗性。我们对这一大型XP患者队列的长期随访结果显示，XP的异质性比以前认识到的要大。我们的数据现在可以为每位XP患者提供个性化的预后信息和管理建议，并为XP蛋白的功能提供新的见解。
Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins.