ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology.
ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology.
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DOI：
10.1016/j.hoc.2012.10.004
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发表时间：
2013-02
影响因子：
2.4
通讯作者：
Tidwell, Timothy
中科院分区：
文献类型：
--
作者：
Horwitz, Marshall S.;Corey, Seth J.;Grimes, H. Leighton;Tidwell, Timothy
关键词：
有两种主要形式的遗传性中性粒细胞减少症：周期性和严重的先天性中性粒细胞减少症（SCN）。周期性中性粒细胞减少症是一种常染色体显性遗传疾病，其中中性粒细胞计数在接近正常水平和接近零之间波动，周期为21天。相反，SCN，也称为Kostmann综合征，由慢性和严重的中性粒细胞减少症组成，具有骨髓中特征性的早幼粒细胞成熟停滞。与周期性中性粒细胞减少症不同，SCN显示出编码粒细胞集落刺激因子受体（G-CSFR）的基因CSF 3R中的体细胞突变的频繁获得，以及发生骨髓增生异常（MDS）和/或急性髓性白血病（AML）的强烈倾向。周期性中性粒细胞减少症是由编码中性粒细胞颗粒丝氨酸蛋白酶、中性粒细胞弹性蛋白酶的基因ELANE（以前称为ELA 2）中的杂合突变引起的。SCN是遗传异质性的，但它最常与ELANE突变相关。虽然ELANE中的一些不同的错义突变表现出表型-基因型相关性，但有时在具有任一形式的遗传性中性粒细胞减少症的患者中发现相同的突变。突变导致产生突变多肽，但没有常见的生化异常，包括对蛋白水解的影响，已被确定。两个不相互排斥的理论已经被提出来解释突变如何产生中性粒细胞减少症。错误定位假说指出，中性粒细胞弹性蛋白酶内的突变或涉及负责其细胞内运输的其他蛋白质，导致中性粒细胞弹性蛋白酶在不适当的亚细胞区室中积聚。错误折叠假说提出突变阻止蛋白质正确折叠，从而诱导内质网（ER）内的应激反应途径。我们讨论了突变本身如何为发病机制提供线索，描述了支持和矛盾的意见，这两种理论，并强调了有关中性粒细胞减少症的病理生理学悬而未决的问题。
There are two main forms of hereditary neutropenia: cyclic and severe congenital neutropenia (SCN). Cyclic neutropenia is an autosomal dominant disorder in which neutrophil counts fluctuate between nearly normal levels and close to zero with 21-day periodicity. In contrast, SCN, also known as Kostmann syndrome, consists of chronic and profound neutropenia, with a characteristic promyelocytic maturation arrest in the bone marrow. Unlike cyclic neutropenia, SCN displays frequent acquisition of somatic mutations in the gene, CSF3R, encoding the Granulocyte Colony-Stimulating Factor Receptor (G-CSFR), and a strong predisposition to developing myelodysplasia (MDS) and/or acute myeloid leukemia (AML). Cyclic neutropenia is caused by heterozygous mutations in the gene, ELANE (formerly known as ELA2), encoding the neutrophil granule serine protease, neutrophil elastase. SCN is genetically heterogeneous, but it is most frequently associated with ELANE mutations. While some of the different missense mutations in ELANE exhibit phenotype-genotype correlation, the same mutations are sometimes found in patients with either form of inherited neutropenia. The mutations lead to production of a mutant polypeptide, but no common biochemical abnormality, including effects on proteolysis, has been identified. Two non-mutually exclusive theories have been advanced to explain how the mutations might produce neutropenia. The mislocalization hypothesis states that mutations within neutrophil elastase or involving other proteins responsible for its intracellular trafficking cause neutrophil elastase to accumulate in inappropriate subcellular compartments. The misfolding hypothesis proposes that mutations prevent the protein from properly folding, thereby inducing the stress response pathway within the endoplasmic reticulum (ER). We discuss how the mutations themselves provide clues into pathogenesis, describe supporting and contradictory observations for both theories, and highlight outstanding questions relating to pathophysiology of neutropenia.
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