Trichothiodystrophy (TTD) is a rare hereditary disease whose prominent feature is brittle hair. Additional clinical signs are physical and neurodevelopmental abnormalities and in about half of the cases hypersensitivity to UV radiation. The photosensitive form of TTD (PS-TTD) is most commonly caused by mutations in the ERCC2/XPD gene encoding a subunit of the transcription/DNA repair complex TFIIH. Here we report novel ERCC2/XPD mutations affecting proper protein folding, which generate thermo-labile forms of XPD associated with thermo-sensitive phenotypes characterized by reversible aggravation of TTD clinical signs during episodes of fever. In patient cells, the newly identified XPD variants result in thermo-instability of the whole TFIIH complex and consequent temperature-dependent defects in DNA repair and transcription. Improving the protein folding process by exposing patient cells to low temperature or to the chemical chaperone glycerol allowed rescue of TFIIH thermo-instability and a concomitant recovery of the complex activities. Besides providing a rationale for the peculiar thermo-sensitive clinical features of these new cases, the present findings demonstrate how variations in the cellular concentration of mutated TFIIH impact the cellular functions of the complex and underlie how both quantitative and qualitative TFIIH alterations contribute to TTD clinical features.

中文翻译：

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TFIIH 稳定恢复热敏性毛硫营养不良症中的 DNA 修复和转录功能障碍

毛硫营养不良症 (TTD) 是一种罕见的遗传性疾病，其显着特征是头发变脆。其他临床症状是身体和神经发育异常，并且在大约一半的病例中对紫外线辐射过敏。TTD 的光敏形式 (PS-TTD) 最常由编码转录/DNA 修复复合体 TFIIH 亚基的ERCC2/XPD基因突变引起。在这里我们报告新的 ERCC2/XPD影响正确蛋白质折叠的突变，产生与热敏表型相关的热不稳定形式的 XPD，其特征是在发烧期间可逆地加重 TTD 临床体征。在患者细胞中，新发现的 XPD 变体导致整个 TFIIH 复合体的热不稳定性以及随之而来的 DNA 修复和转录中的温度依赖性缺陷。通过将患者细胞暴露于低温或化学分子伴侣甘油来改善蛋白质折叠过程，可以挽救 TFIIH 的热不稳定性并伴随恢复复杂的活动。除了为这些新病例的特殊热敏临床特征提供基本原理外，