Identification of new RECQL4 mutations in Caucasian Rothmund-Thomson patients and analysis of sensitivity to a wide range of genotoxic agents
Identification of new RECQL4 mutations in Caucasian Rothmund-Thomson patients and analysis of sensitivity to a wide range of genotoxic agents
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DOI：
10.1016/j.mrfmmm.2008.06.002
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发表时间：
2008-08-25
影响因子：
2.3
通讯作者：
Daya-Grosjean, Leela
中科院分区：
文献类型：
--
作者：
Caseira Cabral, Rosa Estela;Queille, Sophie;Daya-Grosjean, Leela
罗斯蒙-汤姆森综合征（RTS）是一种罕见的隐性常染色体疾病，表现为基因组不稳定性和临床异质性，伴有生长缺陷、皮肤和骨骼缺陷、过早衰老症状和癌症易感性。RTS患者的一个子集呈现RECQL 4基因的突变，RECQ基因是DNA解旋酶家族的成员，包括RECQL 2（BLM）和RECQL 3（WRN）基因，分别在癌症倾向的Bloom和Werner综合征中有缺陷。对6名临床诊断的RTS患者的RECQL 4基因分析显示，5名患者（包括2名同胞）有8个主要位于解旋酶结构域的突变，3名患者有2个突变。这些改变包括4个错义突变，1个无义突变和相同的移码缺失，在3例患者中发现外显子9中的g.2881 delG。7个RECQL 4多态性，其中两个是新的，也已确定。来自这些RTS患者的原代RTS成纤维细胞对多种遗传毒性剂不敏感，包括电离或紫外线照射、氮芥、4 NQO、8-MOP、Cis-Pt、MMC、H2 O2、HU或UV加咖啡因，这些遗传毒性剂可能与此处确定的RECQL 4改变相关。这与DNA损伤敏感的Bloom和Werner细胞形成对比，并强调了维持基因组完整性所需的不同细胞途径中涉及的众多RecQ蛋白功能的复杂性。(c)2008 Elsevier B. V.保留所有权利。
Rothmund-Thomson syndrome (RTS), a rare recessive autosomal disorder, presents genome instability and clinical heterogeneity with growth deficiency, skin and bone defects, premature aging symptoms and cancer susceptibility. A subset of RTS patients presents mutations of the RECQL4 gene, member of the RecQ family of DNA helicases, including the RECQL2 (BLM) and RECQL3 (WRN) genes, defective in the cancer prone Bloom and Werner syndromes, respectively. Analysis of the RECQL4 gene in six clinically diagnosed RTS patients shows five patients, including two siblings, with eight mutations mainly located in the helicase domain, three patients presenting two mutations. The alterations include four missense mutations, one nonsense mutation and the same frameshift deletion, g.2881 delG in exon 9 found in three patients. Seven RECQL4 polymorphisms, two being new, have also been identified. Primary RTS fibroblasts from these RTS patients show no sensitivity to a wide variety of genotoxic agents including ionizing or ultraviolet irradiation, nitrogen mustard, 4NQO, 8-MOP, Cis-Pt, MMC, H2O2, HU, or UV plus caffeine which could be related to the RECQL4 alterations identified here. This is in contrast with the DNA damage sensitive Bloom and Werner cells and highlights the complexity of the numerous RecQ protein functions implicated in the different cellular pathways required for maintaining genomic integrity. (c) 2008 Elsevier B.V. All rights reserved.