Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype.
Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype.
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DOI：
10.1158/2159-8290.cd-14-1156
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发表时间：
2015-02
期刊：
影响因子：
28.2
通讯作者：
Greenberg RA
中科院分区：
文献类型：
--
作者：
Sawyer SL;Tian L;Kähkönen M;Schwartzentruber J;Kircher M;University of Washington Centre for Mendelian Genomics;FORGE Canada Consortium;Majewski J;Dyment DA;Innes AM;Boycott KM;Moreau LA;Moilanen JS;Greenberg RA
BRCA依赖的DNA链间交联(ICL)修复缺陷与乳腺癌易感性和罕见的发育综合征Fanconi贫血(FA)密切相关。在ICL修复过程中，真正的FA蛋白BRCA2(FANCD1)、PALB2(FANCN)和BRIP1(FANCJ)与BRCA1相互作用。然而，由于缺乏BRCA1双等位基因突变患者的详细表型和细胞特征，无法将BRCA1指定为明确的FA易感基因。在这里，我们报告了一名患有与FA样疾病和23岁乳腺癌相一致的多个先天性异常的女性，存在双等位基因BRCA1突变。患者细胞显示BRCA1(FANCS)和RAD51缺乏对DNA损伤部位的定位，并伴有放射状染色体形成和对ICL诱导剂的超敏。这些功能的恢复是通过异位导入BRCA1转基因实现的。这些观察结果支持BRCA1是一种新的Fanconi贫血亚型(FA-S)。
Deficiency in BRCA dependent DNA inter-strand crosslink (ICL) repair is intimately connected to breast cancer susceptibility and to the rare developmental syndrome, Fanconi Anemia (FA). Bona fide FA proteins, BRCA2 (FANCD1), PALB2 (FANCN), and BRIP1 (FANCJ) interact with BRCA1 during ICL repair. However, lack of detailed phenotypic and cellular characterization of a patient with biallelic BRCA1 mutations has precluded assignment of BRCA1 as a definitive FA susceptibility gene. Here we report the presence of biallelic BRCA1 mutations in a woman with multiple congenital anomalies consistent with a FA-like disorder and breast cancer at age 23. Patient cells exhibited deficiency in BRCA1 (FANCS) and Rad51 localization to DNA damage sites, combined with radial chromosome formation and hypersensitivity to ICL inducing agents. Restoration of these functions was achieved by ectopic introduction of a BRCA1 transgene. These observations provide evidence in support of BRCA1 as a new Fanconi anemia subtype (FA-S).