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首页> 外文期刊>Experimental dermatology >Functional and molecular genetic analyses of nine newly identified XPD-deficient patients reveal a novel mutation resulting in TTD as well as in XP/CS complex phenotypes
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Functional and molecular genetic analyses of nine newly identified XPD-deficient patients reveal a novel mutation resulting in TTD as well as in XP/CS complex phenotypes

机译：对九名新发现的XPD缺陷患者的功能和分子遗传学分析揭示了导致TTD以及XP / CS复杂表型的新突变

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The xeroderma pigmentosum (XP) group D protein is involved in nucleotide excision repair (NER) as well as in basal transcription. Determined by the type of XPD mutation, six different clinical entities have been distinguished: XP, XP with neurological symptoms, trichothiodystrophy (TTD), XP/TTD complex, XP/Cockayne syndrome (CS) complex or the cerebro-oculo-facio-skeletal syndrome (COFS). We identified nine new XPD-deficient patients. Their fibroblasts showed reduced post-UV cell survival, reduced NER capacity, normal XPD mRNA expression and partly reduced XPD protein expression. Six patients exhibited a XP phenotype in accordance with established XP-causing mutations (c.2079G>A, p.R683Q; c.2078G>T, p.R683W; c.1833G>T, p.R601L; c.1878G>C, p.R616P; c.1878G>A, p.R616Q). One TTD patient was homozygous for the known TTD-causing mutation p.R722W (c.2195C>T). Two patients were compound heterozygous for a TTD-causing mutation (c.366G>A, p.R112H) and a novel p.D681H (c.2072G>C) amino acid exchange, but exhibited different TTD and XP/CS complex phenotypes, respectively. Interestingly, the XP/CS patient's cells exhibited a reduced but well detectable XPD protein expression compared with hardly detectable XPD expression of the TTD patient's cells. Same mutations with different clinical outcomes in NER-defective patients demonstrate the complexity of phenotype-genotype correlations, for example relating to additional genetic variations (parental consanguinity), different allelic expression due to SNPs or differences in the methylation status.
机译：色素干皮病（XP）D组蛋白参与核苷酸切除修复（NER）和基础转录。根据XPD突变的类型，已区分出六个不同的临床实体：XP，具有神经系统症状的XP，硫代营养不良（TTD），XP / TTD复合体，XP / Cockayne综合征（CS）复合体或脑-眼-筋膜-骨骼综合症（COFS）。我们确定了9名新的XPD缺陷患者。他们的成纤维细胞显示出降低的UV后细胞存活率，降低的NER能力，正常的XPD mRNA表达以及部分降低的XPD蛋白表达。六名患者表现出与既定的XP致突变一致的XP表型（c.2079G> A，p.R683Q; c.2078G> T，p.R683W; c.1833G> T，p.R601L; c.1878G> C ，p.R616P; c.1878G> A，p.R616Q）。一名TTD患者因已知的引起TTD的突变p.R722W（c.2195C> T）是纯合的。两名患者因发生TTD突变（c.366G> A，p.R112H）和新型p.D681H（c.2072G> C）氨基酸交换为复合杂合子，但表现出不同的TTD和XP / CS复杂表型，分别。有趣的是，与难以检测到的TTD患者细胞的XPD表达相比，XP / CS患者的细胞显示出降低的但可检测的XPD蛋白表达。 NER缺陷患者中具有不同临床结果的相同突变表明表型与基因型相关性的复杂性，例如与其他遗传变异（父母血缘关系），由于SNP引起的等位基因表达不同或甲基化状态不同有关。

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