Genome Instability and DNA Repair Group, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
Blood. 2012 Jul 5;120(1):86-9. doi: 10.1182/blood-2012-04-420604. Epub 2012 May 18.
Fanconi anemia (FA) is a rare bone marrow failure disorder with defective DNA interstrand crosslink repair. Still, there are FA patients without mutations in any of the 15 genes individually underlying the disease. A candidate protein for those patients, FA nuclease 1 (FAN1), whose gene is located at chromosome 15q13.3, is recruited to stalled replication forks by binding to monoubiquitinated FANCD2 and is required for interstrand crosslink repair, suggesting that mutation of FAN1 may cause FA. Here we studied clinical, cellular, and genetic features in 4 patients carrying a homozygous 15q13.3 micro-deletion, including FAN1 and 6 additional genes. Biallelic deletion of the entire FAN1 gene was confirmed by failure of 3'- and 5'-PCR amplification. Western blot analysis failed to show FAN1 protein in the patients' cell lines. Chromosome fragility was normal in all 4 FAN1-deficient patients, although their cells showed mild sensitivity to mitomycin C in terms of cell survival and G(2) phase arrest, dissimilar in degree to FA cells. Clinically, there were no symptoms pointing the way to FA. Our results suggest that FAN1 has a minor role in interstrand crosslink repair compared with true FA genes and exclude FAN1 as a novel FA gene.
范可尼贫血症（FA）是一种罕见的骨髓衰竭疾病，其 DNA 链间交联修复存在缺陷。然而，仍有 FA 患者的任何一个致病基因均未发生突变。FA 核酸内切酶 1（FAN1）是这些患者的候选蛋白，其基因位于 15 号染色体 q13.3 上，通过与单泛素化的 FANCD2 结合而被招募到停滞的复制叉上，并参与链间交联修复，这表明 FAN1 的突变可能导致 FA。在这里，我们研究了 4 名携带同源 15q13.3 微缺失的患者的临床、细胞和遗传特征，包括 FAN1 和另外 6 个基因。通过 3'-和 5'-PCR 扩增失败，证实了整个 FAN1 基因的双等位基因缺失。患者的细胞系中未能检测到 FAN1 蛋白的 Western blot 分析。尽管这些细胞在细胞存活和 G2 期阻滞方面对丝裂霉素 C 的敏感性轻度增加，与 FA 细胞的程度不同，但 4 名 FAN1 缺陷患者的染色体脆性均正常。在临床上，没有指向 FA 的症状。我们的结果表明，与真正的 FA 基因相比，FAN1 在链间交联修复中发挥的作用较小，并排除了 FAN1 作为一种新的 FA 基因。
