Weeda G, Eveno E, Donker I, Vermeulen W, Chevallier-Lagente O, Taïeb A, Stary A, Hoeijmakers J H, Mezzina M, Sarasin A
MGC--Department of Cell Biology and Genetics, Erasmus University, Rotterdam, The Netherlands.
Am J Hum Genet. 1997 Feb;60(2):320-9.
Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and nails, mental retardation, impaired sexual development, and ichthyosis. Photosensitivity has been reported in approximately 50% of the cases, but no skin cancer is associated with TTD. Virtually all photosensitive TTD patients have a deficiency in the nucleotide excision repair (NER) of UV-induced DNA damage that is indistinguishable from that of xeroderma pigmentosum (XP) complementation group D (XP-D) patients. DNA repair defects in XP-D are associated with two additional, quite different diseases; XP, a sun-sensitive and cancer-prone repair disorder, and Cockayne syndrome (CS), a photosensitive condition characterized by physical and mental retardation and wizened facial appearance. One photosensitive TTD case constitutes a new repair-deficient complementation group, TTD-A. Remarkably, both TTD-A and XP-D defects are associated with subunits of TFIIH, a basal transcription factor with a second function in DNA repair. Thus, mutations in TFIIH components may, on top of a repair defect, also cause transcriptional insufficiency, which may explain part of the non-XP clinical features of TTD. Besides XPD and TTDA, the XPB gene product is also part of TFIIH. To date, three patients with the remarkable conjunction of XP and CS but not TTD have been assigned to XP complementation group B (XP-B). Here we present the characterization of the NER defect in two mild TTD patients (TTD6VI and TTD4VI) and confirm the assignment to X-PB. The causative mutation was found to be a single base substitution resulting in a missense mutation (T119P) in a region of the XPB protein completely conserved in yeast, Drosophila, mouse, and man. These findings define a third TTD complementation group, extend the clinical heterogeneity associated with XP-B, stress the exclusive relationship between TTD and mutations in subunits of repair/transcription factor TFIIH, and strongly support the concept of "transcription syndromes."
毛发硫营养不良症（TTD）是一种罕见的常染色体隐性疾病，其特征为毛发和指甲硫缺乏、变脆，智力发育迟缓，性发育受损以及鱼鳞病。约50%的病例有光敏性，但TTD与皮肤癌无关。几乎所有光敏性TTD患者都存在紫外线诱导的DNA损伤核苷酸切除修复（NER）缺陷，这与着色性干皮病（XP）互补组D（XP-D）患者的情况无法区分。XP-D中的DNA修复缺陷与另外两种截然不同的疾病相关；XP是一种对阳光敏感且易患癌症的修复障碍疾病，而科凯恩综合征（CS）是一种光敏性疾病，其特征为身心发育迟缓以及面容憔悴。一例光敏性TTD病例构成了一个新的修复缺陷互补组，即TTD-A。值得注意的是，TTD-A和XP-D缺陷均与TFIIH的亚基相关，TFIIH是一种基础转录因子，在DNA修复中具有第二种功能。因此，TFIIH组分的突变除了导致修复缺陷外，还可能引起转录不足，这或许可以解释TTD的部分非XP临床特征。除了XPD和TTDA外，XPB基因产物也是TFIIH的一部分。迄今为止，已有三名具有XP和CS显著联合症状但无TTD症状的患者被归入XP互补组B（XP-B）。在此，我们展示了两名轻度TTD患者（TTD6VI和TTD4VI）NER缺陷的特征，并确认其归入X-PB。发现致病突变是一个单碱基替换，导致XPB蛋白在酵母、果蝇、小鼠和人类中完全保守的区域出现错义突变（T119P）。这些发现定义了第三个TTD互补组，扩展了与XP-B相关的临床异质性，强调了TTD与修复/转录因子TFIIH亚基突变之间的排他性关系，并有力地支持了“转录综合征”的概念。
