Laboratory of Molecular Genetics, Department of Physiology and Biochemistry, University of Malta, Msida, Malta.
Nat Genet. 2010 Sep;42(9):801-5. doi: 10.1038/ng.630. Epub 2010 Aug 1.
Hereditary persistence of fetal hemoglobin (HPFH) is characterized by persistent high levels of fetal hemoglobin (HbF) in adults. Several contributory factors, both genetic and environmental, have been identified but others remain elusive. HPFH was found in 10 of 27 members from a Maltese family. We used a genome-wide SNP scan followed by linkage analysis to identify a candidate region on chromosome 19p13.12-13. Sequencing revealed a nonsense mutation in the KLF1 gene, p.K288X, which ablated the DNA-binding domain of this key erythroid transcriptional regulator. Only family members with HPFH were heterozygous carriers of this mutation. Expression profiling on primary erythroid progenitors showed that KLF1 target genes were downregulated in samples from individuals with HPFH. Functional assays suggested that, in addition to its established role in regulating adult globin expression, KLF1 is a key activator of the BCL11A gene, which encodes a suppressor of HbF expression. These observations provide a rationale for the effects of KLF1 haploinsufficiency on HbF levels.
遗传性胎儿血红蛋白持续存在症（HPFH）的特征是成年人中持续高水平的胎儿血红蛋白（HbF）。已经确定了一些遗传和环境的促成因素，但其他因素仍难以捉摸。在来自马耳他的一个家庭的 27 名成员中发现了 10 名 HPFH 患者。我们使用全基因组 SNP 扫描，然后进行连锁分析，在 19p13.12-13 染色体上确定了一个候选区域。测序显示 KLF1 基因中的无义突变，p.K288X，该突变破坏了这个关键的红细胞转录调节因子的 DNA 结合域。只有具有 HPFH 的家族成员是该突变的杂合携带者。对原代红细胞祖细胞的表达谱分析显示，HPFH 个体的样本中 KLF1 靶基因下调。功能测定表明，除了其在调节成人珠蛋白表达中的既定作用外，KLF1 还是 BCL11A 基因的关键激活剂，该基因编码 HbF 表达的抑制剂。这些观察结果为 KLF1 单倍不足对 HbF 水平的影响提供了依据。
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