KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome
KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome
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DOI：
10.1182/blood-2014-08-590968
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发表时间：
2015-04-09
期刊：
影响因子：
20.3
通讯作者：
Perkins, Andrew C.
中科院分区：
文献类型：
--
作者：
Magor, Graham W.;Tallack, Michael R.;Perkins, Andrew C.
我们描述了一例严重的新生儿贫血与核黄疸所造成的复合杂合性无效突变KLF 1，每一个无症状的父母继承。其中一个突变是新的。这是第一个描述的KLF 1-null人类病例。由于KLF 1第二锌指基因的显性突变，严重非球形红细胞溶血性贫血、黄疸、肝脾肿大和显著的成红细胞增多症的表型比先天性红细胞生成不良性贫血IV型更严重。HbF在儿童期的表达水平非常高（>70%），这与KLF 1在人类血红蛋白转换中的关键作用一致。我们对循环成红细胞进行了RNA-seq，发现人KLF 1的作用与小鼠Klf 1相似，可以协调构建红细胞所需的许多基因的表达，包括编码球蛋白、细胞骨架成分、血红蛋白稳定蛋白、血红素合成酶、细胞周期调节因子和血型抗原的基因。我们确定了新的KLF 1靶基因，包括KIF 23和KIF 11，它们是正常胞质分裂所需的。我们还确定了KLF 1在自噬，全局转录控制和RNA剪接中的新作用。我们建议，KLF 1的丢失应考虑在其他原因不明的情况下，严重的新生儿NSHA或胎儿水肿。
We describe a case of severe neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice, hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenital dyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found that human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis.