Molecular pathogenesis of Fanconi anemia

范可尼贫血的分子发病机制

基本信息

批准号：
16590928
负责人：
YAMASHITA Takayuki
金额：
$ 2.37万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590928/
关键词：
Fanconi anemia bone marrow failure DNA repair genetic reversion somatic mosaicism methylation tumor suppressor gene シャペロンユビキチン化プロテアソーム

项目摘要

Fanconi anemia (FA) is a genetically heterogeneous inherited disorder characterized by bone marrow failure and congenital anomalies. Although an increasing number of reports suggest that reverse mosaicism noted in peripheral blood lymphocytes (PBL) is associated with mild hematopoietic failure in FA, direct examination of myeloid cells have been done in few cases. We found a patient with prolonged mild pancytopenia in whom proliferation of revertant cells was detected in mature myeloid cells but not in PBL. While this patient had inherited heterozygous mutations, 2546delC and 3720-3724del, in the major Fanconi anemia gene FANCA, lymphoblastoid cells from the patient had 2546C>T instead of 2546delC, resulting in expression of a functional missense protein. Since the identical reversion was detected in polymorphonuclear granulocytes and mononuclear phagocytes, sustained hematopoiesis in the patient is attributed to selective growth advantage of revertant myeloid cells. It is noteworthy t … More hat such a myeloid lineage-selective mosaicism is overlooked in routine examination of PBL. Recognition of this status will expand the role of reverse mosaicism in the pathophysiology of FA. Bone marrow failure in FA often shows progression to myelodysplastic syndrome (MDS) and leukemia, which may be attributed to mutations of oncogenes and tumor suppressor genes based on DNA repair deficiency. However, specific mutations of these genes have not been identified in FA leukemic cells. We hypothesized that epigenetic abnormalities may be associated with the pathophysiology of FA. To address this question, we analyzed promoter methylation of five tumor suppressor genes, p15, p16. DAP kinase, RAR-β, E-cadherin. The results showed that 8 of 11 patients (72.7%) had hypermethylation in one or more of these genes. The methylation abnormalities were observed more frequently in patients with MDS than in those without MDS. These results suggest that epigenetic abnormalities might be involbed in leukmogensis in FA. Less

Fanconi贫血（FA）是一种遗传性异质遗传疾病，其特征是骨髓衰竭和先天性。 Re Myloid细胞，但在PBL中不遗传杂合突变，2546delc和3720-3724del，在您的主要fanconi贫血基因基因上，患者的淋巴细胞细胞具有2546c> t在多形核中检测到相同的反向，而单核的吞噬细胞归因于恢复的髓样细胞的选择性生长优势。基于DNA修复的进展激酶，RAR-β，E-cadherin。