Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia
Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia
复制标题
DOI：
10.1182/blood.v96.7.2317.h8002317_2317_2322
复制
发表时间：
2000-10-01
期刊：
影响因子：
20.3
通讯作者：
Horwitz, M
中科院分区：
文献类型：
--
作者：
Dale, DC;Person, RE;Horwitz, M
先天性中性粒细胞减少症和循环中性粒细胞减少症是中性粒细胞产生障碍，易使患者复发性细菌感染。最近，常染色体显性环状中性粒细胞减少症的基因座被定位到染色体19p13.3，这种疾病现在可归因于编码中性粒细胞弹性酶（ELA2基因）的基因突变。作者推测先天性中性粒细胞减少症也是由中性粒细胞弹性酶突变引起的。先天性中性粒细胞减少症、循环中性粒细胞减少症或Shwachman-Diamond综合征的患者被提交到严重慢性中性粒细胞减少症国际登记处。转诊医师提供血液学和临床资料。通过对中性粒细胞ELA2基因的5个外显子和侧翼区域的20个碱基进行PCR扩增的基因组DNA测序进行突变分析。从骨髓单核细胞提取RNA；用于确定受影响的患者是否表达正常和异常转录本。25例先天性中性粒细胞减少症患者中有22例有18种不同的杂合突变。4例循环中性粒细胞减少症患者中4例发生突变，3例Shwachman-Diamond综合征患者中0例发生突变。对于5例先天性中性粒细胞减少患者，预测突变会改变RNA剪接或转录本结构，逆转录- pcr显示正常和异常转录本的表达。在环状中性粒细胞减少症中，突变似乎聚集在分子的活性位点附近，而在先天性中性粒细胞减少症中，突变主要受相反面影响。这项研究表明，编码中性粒细胞弹性酶的基因突变可能是严重先天性中性粒细胞减少症的最常见原因，也是散发性和常染色体显性循环中性粒细胞减少症的原因。（Blood. 2000;96:2317-2322） (C) 2000年由美国血液学会出版。
Congenital neutropenia and cyclic neutropenia are disorders of neutrophil production predisposing patients to recurrent bacterial infections. Recently the locus for autosomal dominant cyclic neutropenia was mapped to chromosome 19p13.3, and this disease is now attributable to mutations of the gene encoding neutrophil elastase (the ELA2 gene). The authors hypothesized that congenital neutropenia is also due to mutations of neutrophil elastase. Patients with congenital neutropenia, cyclic neutropenia, or Shwachman-Diamond syndrome were referred to the Severe Chronic Neutropenia International Registry. Referring physicians provided hematologic and clinical data. Mutational analysis was performed by sequencing polymerase chain reaction (PCR)-amplified genomic DNA for each of the 5 exons of the neutrophil ELA2 gene and 20 bases of the flanking regions. RNA from bone marrow mononuclear cells was; used to determine if the affected patients expressed both the normal and the abnormal transcript. Twenty-two of 25 patients with congenital neutropenia had 18 different heterozygous mutations. Four of 4 patients with cyclic neutropenia and 0 of 3 patients with Shwachman-Diamond syndrome had mutations. For 5 patients with congenital neutropenia having mutations predicted to alter RNA splicing or transcript structure, reverse transcriptase-PCR showed expression of both normal and abnormal transcripts. In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the opposite face was predominantly affected by the mutations found in congenital neutropenia. This study indicates that mutations of the gene encoding neutrophil elastase are probably the most common cause for severe congenital neutropenia as well as the cause for sporadic and autosomal dominant cyclic neutropenia. (Blood. 2000;96:2317-2322) (C) 2000 by The American Society of Hematology.