Xeroderma pigmentosum (XP) group D, a severe disease often typified by extreme sun sensitivity, can be caused by ERCC2 mutations. ERCC2 encodes an adenosine triphosphate (ATP)-dependent DNA helicase, namely XP group D protein (XPD). The XPD, one of ten subunits of the transcription factor TFIIH, plays a critical role in the nucleotide-excision repair (NER) pathway. Mutations in XPD that affect the NER pathway can lead to neurological degeneration and skin cancer, which are the most common causes of death in XP patients. Here, we present detailed phenotypic information on a Vietnamese family in which four members were affected by XP with extreme sun sensitivity. Genomic analysis revealed a compound heterozygous mutation of ERCC2 that affected family members and single heterozygous mutations in unaffected family members. We identified a novel, nonsense mutation in one allele of ERCC2 (c.1354C > T, p.Q452X) and a known missense mutation in the other allele (c.2048G > A, p.R683Q). Fibroblasts isolated from the compound heterozygous subject also failed to recover from UV-driven DNA damage, thus recapitulating aspects of XP syndrome in vitro. We describe a novel ERCC2 variant that leads to the breakdown of the NER pathway across generations of a family presenting with severe XP.

中文翻译：

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患有色素性干皮病综合征 D 组的越南家族中出现了一种新的 ERCC2 无义突变。

着色性干皮病 (XP) D 组是一种严重的疾病，通常以极度阳光敏感性为代表，可能由 ERCC2 突变引起。ERCC2 编码三磷酸腺苷 (ATP) 依赖性 DNA 解旋酶，即 XP D 组蛋白 (XPD)。XPD 是转录因子 TFIIH 的 10 个亚基之一，在核苷酸切除修复 (NER) 途径中发挥着关键作用。影响 NER 通路的 XPD 突变可导致神经退行性变和皮肤癌，这是 XP 患者最常见的死亡原因。在这里，我们提供了一个越南家庭的详细表型信息，该家庭的四名成员受到了对阳光极度敏感的 XP 的影响。基因组分析揭示了影响家庭成员的 ERCC2 复合杂合突变，以及未受影响的家庭成员的单一杂合突变。我们在 ERCC2 的一个等位基因（c.1354C > T，p.Q452X）中发现了一种新的无义突变，在另一个等位基因（c.2048G > A，p.R683Q）中发现了一种已知的错义突变。从复合杂合受试者中分离出的成纤维细胞也未能从紫外线驱动的 DNA 损伤中恢复，从而在体外重现了 XP 综合征的各个方面。我们描述了一种新的 ERCC2 变体，该变体会导致患有严重 XP 的家庭几代人的 NER 通路崩溃。