Study of molecular pathogenesis of Fanconi anemia

范可尼贫血的分子发病机制研究

基本信息

批准号：
14570963
负责人：
YAMASHITA Takayuki
金额：
$ 2.24万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

Fanconi anemia is an autosomal recessive disorder of hematopoiesis with at least 11 genetically different groups, characterized by cellular hypersensitivity to DNA cross-linkers and chromosome instability. To date, 8 genes have been identified. A multiprotein complex including these gene products, FANCAICJE/F/G/L is required for activation of FANCD2 into a monoubiquitinated form. This active form affects genomic instability in collaboration with BRCA1 and BRCA2IFANCD1. In this project, we studied functions of FANCA mutants with amino acid substitution in its N-terminal region including nuclear localization signal and FANCG-binding sites. Our results indicate that formation of a stable complex including FANCAICIE/FIGIL is not essential for FANCD2 activation. It seems that nuclear import of FANCA/L complex palys a central role in this pathway, and that FANCG negatively regulates nuclear import of FANCA. Furthermore, we identified Hsc7O as a FANCA-binding protein. A dominant-negative form of Hsc7O and 17-AAG, a specific inhibitor of Hsp9O, inhibited nuclear localization of FANCA, suggesting that a chaperone complex including Hsc7O is required for nuclear import of FANCA. We identified FANCA mutations in 27 Japanese FA patients and found novel molecular mechanisms of generation of large deletions in this gene. We found that long-term remission of bone marrow failurewas associated with myeloid lineage-selective expansion of cells with reversion in a patient. This case suggests the clinical usefulness of gene therapy.

Fanconi贫血是一种至少11个遗传不同组的造血症的常染色体隐性障碍，其特征是对DNA交叉链链链和染色体不稳定性的细胞超敏反应。迄今为止，已经确定了8个基因。包括这些基因产物的多蛋白络合物，fancaicje/f/g/l是将fancd2激活成单液化形式所必需的。这种主动形式会与BRCA1和BRCA2IFANCD1合作影响基因组不稳定性。在这个项目中，我们研究了其在其N末端区域中具有氨基酸取代的FANCA突变体的功能，包括核定位信号和粉丝结合位点。我们的结果表明，稳定的复合物的形成在内，包括Fancaicie/Figil对于fancd2激活并不是必需的。似乎Fanca/L Complex的核进口在这一途径中起着核心作用，而Fancg对Fanca的核进口进行了负面调节。此外，我们将HSC7O鉴定为一种fanca结合蛋白。 HSP9O的特定抑制剂HSC7O和17-AAG的主要阴性形式抑制了FANCA的核定位，这表明包括HSC7O在内的伴侣综合体是FANCA的核进口所必需的。我们确定了27名日本FA患者的FANCA突变，并发现了该基因中大缺失产生的新型分子机制。我们发现，骨髓衰竭的长期缓解与患者恢复细胞的髓样谱系选择性扩张相关。该病例表明基因治疗的临床实用性。