Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3):: Xeroderma pigmentosum without and with Cockayne syndrome
Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3):: Xeroderma pigmentosum without and with Cockayne syndrome
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DOI：
10.1002/humu.20392
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发表时间：
2006-11-01
期刊：
影响因子：
3.9
通讯作者：
Kraemer, Kenneth H.
中科院分区：
文献类型：
--
作者：
Oh, Kyu-Seon;Khan, Sikandar G.;Kraemer, Kenneth H.
着色性干皮病B型（XPB）基因（ERCC 3），一种参与核苷酸切除修复（NER）的DNA解旋酶和基础转录因子TFIIH的必需亚基的缺陷仅在三个家族中描述。我们报告了三个新的XPB家族：一个有两个姐妹相对轻度着色性干皮病（XT）的症状，以前没有与XPB突变和两个严重的XP/Cockayne综合征（CS）复杂的症状。所有XP-B细胞的NER和紫外线（UV）后细胞活力均降低。令人惊讶的是，来自较温和的XP姐妹篇的细胞具有与先前在两个轻度XP/CS复合体兄弟中报道的相同的错义突变（c.296T > C，p.F99S）。这些细胞的XTB蛋白水平高于严重受累的XP/CS复合体患者。具有p.F99S突变的XTB表达载体部分补充了XP-B细胞中的NER缺陷。三个严重受累的XP/CS复合体家族都在一个等位基因中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个氨基酸的改变，产生部分NER互补。这种有限的突变数量可能反映了这种与生命相容的重要蛋白质的变化范围非常有限。我们发现第二个等位基因中的新突变在所有五个XT或XP/CS复合家族中产生显着截短的蛋白质：c.1273C > T，p.R425X; c-471+IG > A，p.K157insTSDSX; C.807- 808 delTT，p.F270X; c. 1421- 1422 insA，p.D474EfsX475;和c. 1633C > T，p.Q545X. XPB的显著表型异质性与轻度患者中的部分活性错义突变相关，而重度XT/CS复合体患者在两个等位基因中均存在无义突变，且XTB蛋白水平低。
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 (XT) 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 XTB protein than the severely affected XP/CS complex patients. An XTB 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 XT or XP/CS complex families: c.1273C > T, p.R425X; c-471+IG > 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 XT/CS complex patients have nonsense mutations in both alleles with low levels of altered XTB proteins.