Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway
Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway
复制标题
DOI：
10.1182/blood-2004-05-1852
复制
发表时间：
2005-02-01
期刊：
影响因子：
20.3
通讯作者：
Gluckman, E
中科院分区：
文献类型：
--
作者：
Soulier, J;Leblanc, T;Gluckman, E
范可尼贫血（FA）的特征是先天性异常、骨髓衰竭、染色体脆性和癌症易感性。目前已鉴定出8个FA相关基因，其产物在FA/BRCA通路中起作用。该途径中的一个关键事件是FANCD 2蛋白的单泛素化，其依赖于多蛋白FA核心复合物。在一些患者中，自发的遗传回复可以纠正FA突变，导致体细胞嵌合。我们通过FANCD 2免疫印迹和染色体断裂试验分析了53例FA患者的FA/BRCA通路。引人注目的是，在8例（15%）患者的外周血淋巴细胞（PBL）中检测到FANCD 2单泛素化。通过比较原代成纤维细胞和PBL，进一步显示了这些患者中的FA逆转。逆转与较高的血细胞计数和临床稳定或改善相关。一旦确定了组成性FANCD 2模式，患者可以基于FA/BRCA途径破坏的水平分类为“FA核心”（上游失活; n = 47，89%）、FA-D2（n = 4，8%）和单克隆下游组（n = 2，4%）。因此，FA-D2和未确定组患者相对常见，并且他们具有更严重的先天性表型。这些结果表明，结合临床和染色体断裂数据，对FA/BRCA通路进行特异性分析，可以对FA患者进行全面表征。(C)2005年，美国血液学会。
Fanconi anemia (FA) is characterized by congenital abnormalities, bone marrow failure, chromosome fragility, and cancer susceptibility. Eight FA-associated genes have been identified so far, the products of which function in the FA/BRCA pathway. A key event in the pathway is the monoubiquitination of the FANCD2 protein, which depends on a multiprotein FA core complex. In a number of patients, spontaneous genetic reversion can correct FA mutations, leading to somatic mosaicism. We analyzed the FA/BRCA pathway in 53 FA patients by FANCD2 immunoblots and chromosome breakage tests. Strikingly, FANCD2 monoubiquitination was detected in peripheral blood lymphocytes (PBLs) in 8 (15%) patients. FA reversion was further shown in these patients by comparison of primary fibroblasts and PBLs. Reversion was associated with higher blood counts and clinical stability or improvement. Once constitutional FANCD2 patterns were determined, patients could be classified based on the level of FA/BRCA pathway disruption, as "FA core" (upstream inactivation; n = 47, 89%), FA-D2 (n = 4, 8%), and an uniclenti led downstream group (n = 2, 4%). FA-D2 and unidentified group patients were therefore relatively common, and they had more severe congenital phenotypes. These results show that specific analysis of the FA/BRCA pathway, combined with clinical and chromosome breakage data, allows a comprehensive characterization of FA patients. (C) 2005 by The American Society of Hematology.