A novel XPD mutation in a compound heterozygote; the mutation in the second allele is present in three homozygous patients with mild sun sensitivity.
A novel XPD mutation in a compound heterozygote; the mutation in the second allele is present in three homozygous patients with mild sun sensitivity.
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复合杂合子中的一种新的 XPD 突变；
DOI：
10.1002/em.21716
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发表时间：
2012
影响因子：
2.8
通讯作者：
Hanawalt,PhilipC
中科院分区：
文献类型：
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作者：
Falik-Zaccai,TziporaC;Erel-Segal,Reut;Horev,Liran;Bitterman-Deutsch,Ora;Koka,Sivan;Chaim,Sara;Keren,Zohar;Kalfon,Limor;Gross,Bella;Segal,Zvi;Orgal,Shlomi;Shoval,Yishay;Slor,Hanoch;Spivak,Graciela;Hanawalt,PhilipC
XPD蛋白作为转录因子TFIIH的十种已知组分之一，在基础转录和核苷酸切除修复（NER）中起关键作用。XPD中的突变可导致DNA修复缺陷性疾病着色性干皮病（XP）、脑硫营养不良（TTD）、脑眼面骨骼综合征，以及XP/Cockayne综合征和XP/TTD等联合表型。我们在这里描述了一个18岁的个体，具有轻度的阳光敏感性，没有神经系统异常，也没有肿瘤，他在一个等位基因中携带p.R683Q突变，在XPD基因的另一个等位基因中携带新的p.R616Q突变。我们还描述了来自一个家庭的4名患者，在XPD中具有相同的p.R683Q突变纯合子，表现出轻度皮肤色素沉着和腱反射丧失。三名纯合子患者出现迟发性皮肤肿瘤，两名患者出现早衰和中度认知功能下降。来自复合杂合个体和来自p.R683Q纯合患者之一的细胞对UV照射表现出相似的反应：活力降低和UV诱导的环丁烷嘧啶二聚体的整体去除缺陷，这意味着缺乏全局基因组NER。来自复合杂合受试者的细胞在UV后也未能恢复RNA合成，表明有缺陷的转录偶联NER。XPD中影响密码子616的突变通常导致功能无效的蛋白质;我们假设杂合子患者的表型仅由p.R683Q等位基因的表达引起。这项研究说明了对阳光敏感的个体进行详细随访的重要性，以确保适当的预防并了解所涉及的遗传性疾病的机制基础。Environ.摩尔诱变剂，2012.© 2012 Wiley Periodicals，Inc.
The XPD protein plays a pivotal role in basal transcription and in nucleotide excision repair (NER) as one of the ten known components of the transcription factor TFIIH. Mutations in XPD can result in the DNA repair‐deficient diseases xeroderma pigmentosum (XP), trichothiodystrophy (TTD), cerebro‐oculo‐facial‐skeletal syndrome, and in combined phenotypes such as XP/Cockayne syndrome and XP/TTD. We describe here an 18‐year‐old individual with mild sun sensitivity, no neurological abnormalities and no tumors, who carries a p.R683Q mutation in one allele, and the novel p.R616Q mutation in the other allele of theXPDgene. We also describe four patients from one family, homozygous for the identical p.R683Q mutation in XPD, who exhibit mild skin pigmentation and loss of tendon reflexes. Three homozygous patients presented with late‐onset skin tumors, and two with features of premature aging and moderate cognitive decline. Cells from the compound heterozygous individual and from one of the patients homozygous for p.R683Q exhibited similar responses to UV irradiation: reduced viability and defective overall removal of UV‐induced cyclobutane pyrimidine dimers, implying deficient global genomic NER. Cells from the compound heterozygous subject also failed to recover RNA synthesis after UV, indicating defective transcription‐coupled NER. Mutations affecting codon 616 inXPDgenerally result in functionally null proteins; we hypothesize that the phenotype of the heterozygous patient results solely from expression of the p.R683Q allele. This study illustrates the importance of detailed follow up with sun sensitive individuals, to ensure appropriate prophylaxis and to understand the mechanistic basis of the implicated hereditary disease. Environ. Mol. Mutagen., 2012. © 2012 Wiley Periodicals, Inc.