Oh Kyu-Seon, Khan Sikandar G, Jaspers N G J, Raams Anja, Ueda Takahiro, Lehmann Alan, Friedmann Peter S, Emmert Steffen, Gratchev Alexi, Lachlan Katherine, Lucassan Anneke, Baker Carl C, Kraemer Kenneth H
DNA Repair Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4258, USA.
Hum Mutat. 2006 Nov;27(11):1092-103. doi: 10.1002/humu.20392.
Defects in the xeroderma pigmentosum type B (XPB) gene (ERCC3), a DNA helicase involved in nucleotide excision repair (NER) and an essential subunit of the basal transcription factor, TFIIH, have been described in only three families. We report three new XPB families: one has two sisters with relatively mild xeroderma pigmentosum (XP) symptoms not previously associated with XPB mutations and two have severe XP/Cockayne syndrome (CS) complex symptoms. All XP-B cells had reduced NER and post-ultraviolet (UV) cell viability. Surprisingly, cells from the milder XP sisters had the same missense mutation (c.296T>C, p.F99S) that was previously reported in two mild XP/CS complex brothers. These cells had higher levels of XPB protein than the severely affected XP/CS complex patients. An XPB expression vector with the p.F99S mutation partially complemented the NER defect in XP-B cells. The three severely affected XP/CS complex families all have the same splice acceptor site mutation (c.2218-6C>A, p.Q739insX42) in one allele. This resulted in alteration of 41 amino acids at the C terminus, producing partial NER complementation. This limited number of mutations probably reflects the very restricted range of alterations of this vital protein that are compatible with life. We found new mutations in the second allele yielding markedly truncated proteins in all five XP or XP/CS complex families: c.1273C>T, p.R425X; c.471+1G>A, p.K157insTSDSX; c.807-808delTT, p.F270X; c.1421-1422insA, p.D474EfsX475; and c.1633C>T, p.Q545X. The remarkable phenotypic heterogeneity of XPB is associated with partially active missense mutations in milder patients while severe XP/CS complex patients have nonsense mutations in both alleles with low levels of altered XPB proteins.
B型着色性干皮病（XPB）基因（ERCC3）存在缺陷，该基因作为一种参与核苷酸切除修复（NER）的DNA解旋酶，是基础转录因子TFIIH的一个必需亚基，目前仅在三个家族中被描述过。我们报告了三个新的XPB家族：一个家族中有两名姐妹患有相对较轻的着色性干皮病（XP）症状，此前未发现与XPB突变相关；另外两个家族患有严重的XP/科凯恩综合征（CS）复合症状。所有XP - B细胞的NER和紫外线（UV）照射后的细胞活力均降低。令人惊讶的是，症状较轻的XP姐妹的细胞具有与之前在两名症状较轻的XP/CS复合症状兄弟中报道的相同错义突变（c.296T>C，p.F99S）。这些细胞中的XPB蛋白水平高于受影响严重的XP/CS复合症状患者。携带p.F99S突变的XPB表达载体部分弥补了XP - B细胞中的NER缺陷。三个受影响严重的XP/CS复合症状家族在一个等位基因中均具有相同的剪接受体位点突变（c.2218 - 6C>A，p.Q739insX42）。这导致C末端41个氨基酸发生改变，产生部分NER互补。这种有限数量的突变可能反映了这种与生命相容的重要蛋白质的改变范围非常有限。我们在所有五个XP或XP/CS复合症状家族的第二个等位基因中发现了新的突变，这些突变产生了明显截短的蛋白质：c.1273C>T，p.R425X；c.471 + 1G>A，p.K157insTSDSX；c.807 - 808delTT，p.F270X；c.1421 - 1422insA，p.D474EfsX475；以及c.1633C>T，p.Q545X。XPB显著的表型异质性与症状较轻患者中的部分活性错义突变相关，而严重的XP/CS复合症状患者在两个等位基因中均存在无义突变，且XPB蛋白水平改变较低。
