Yagasaki Hiroshi, Hamanoue Satoshi, Oda Tsukasa, Nakahata Tatsutoshi, Asano Shigetaka, Yamashita Takayuki
Division of Genetic Diagnosis, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Hum Mutat. 2004 Dec;24(6):481-90. doi: 10.1002/humu.20099.
Fanconi anemia (FA) is a rare autosomal recessive disorder of hematopoiesis, with at least 11 complementation groups. FANCA, a gene for group A, accounts for the majority of FA patients. Previous studies of FANCA mutations revealed high allelic heterogeneity, frequent occurrence of large deletions, and interpopulation differences. However, systematic mutational analysis, including gene dosage assay to detect large deletions, has not been documented for Asian populations. A newly developed TaqMan quantitative PCR-based gene dosage assay, combined with sequencing of exons and cDNA fragments, allowed for detection of 48 mutant alleles of FANCA in 27 (77%) of 35 unrelated Japanese FA families with no detectable mutations in FANCC or FANCG. We identified 29 different mutations (21 nucleotide substitutions or small deletions/insertions and eight large deletions), at least 20 of which were novel. The FANCA mutational spectrum of the Japanese was different from that of other ethnic groups so far studied. This is the largest scale of mutation analysis of FANCA in the Japanese population. Characterization of these mutations provided new information regarding the mutagenesis mechanisms and structure-function relationship of FANCA. Specifically, our data suggest that diverse mechanisms including nonhomologous recombination as well as Alu-mediated homologous recombination are involved in the generation of large deletions in FANCA.
范可尼贫血（FA）是一种罕见的常染色体隐性造血障碍疾病，至少有11个互补组。A组基因FANCA是大多数FA患者的致病原因。以往对FANCA突变的研究显示出高度的等位基因异质性、大缺失的频繁发生以及人群间差异。然而，尚未有针对亚洲人群进行包括检测大缺失的基因剂量分析在内的系统突变分析的文献报道。一种新开发的基于TaqMan定量PCR的基因剂量分析方法，结合外显子和cDNA片段测序，在35个不相关的日本FA家族中的27个（77%）检测到了48个FANCA突变等位基因，这些家族中FANCC或FANCG未检测到突变。我们鉴定出29种不同的突变（21种核苷酸替换或小缺失/插入以及8种大缺失），其中至少20种是新发现的。日本人的FANCA突变谱与迄今为止研究的其他种族不同。这是日本人群中最大规模的FANCA突变分析。这些突变的特征为FANCA的诱变机制和结构-功能关系提供了新信息。具体而言，我们的数据表明，包括非同源重组以及Alu介导的同源重组在内的多种机制参与了FANCA中大缺失的产生。
