Genetic characterization of myeloperoxidase deficiency in Italy
Genetic characterization of myeloperoxidase deficiency in Italy
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DOI：
10.1002/humu.20027
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发表时间：
2004-01-01
期刊：
影响因子：
3.9
通讯作者：
Romano, M
中科院分区：
文献类型：
--
作者：
Marchetti, C;Patriarca, P;Romano, M
遗传性髓过氧化物酶缺乏症(MPOD)是最常见的中性粒细胞生化缺陷，以过氧化物酶活性缺乏为特征。为了扩大意大利遗传性MPOD的流行病学研究，进行了人群筛查以检测MPO基因的突变。在分析的大约40,000个个体中，确定了7个部分和8个全部MPO缺陷的受试者。这些受试者的基因特征显示存在三个已知的突变(c.752T>；C、c.1705C>；T和c.1566_1579del14)和六个新突变：四个错义突变(c.995C>；T、c.1112A>；G、c.1715T>；G和c.1927T>；C)，然后是外显子3内含腺嘌呤的缺失(c.325delA)和内含子11 3‘剪接点的突变(c.2031-2A>；C)。这些新的错义突变导致了残基p.A332V、p.D371G、p.L572W和p.W643R的替换，并对其潜在的结构变化进行了讨论。C.325delA缺失导致阅读框架移位，并在前肽中出现提前终止密码子。然后，考虑到从MPO缺陷者身上获取骨髓标本来研究体内MPO mRNA剪接的困难，我们建立了一个真核表达系统，以研究C.2031-2A和GT；C突变是如何改变MPO前mRNA剪接的。观察到位于真实3‘剪接点上游109nt的一个隐蔽的3’剪接点被激活。109位碱基的插入会导致阅读框的移位，从而导致缺乏酶活性的异常MPO前体的产生。(C)2004年Wiley-Liss公司
Hereditary myeloperoxidase (MPO) deficiency (MPOD) is the most common neutrophil biochemical defect, and is characterized by a lack of peroxidase activity. In order to extend the epidemiological studies on hereditary MPOD in Italy, a population screening was carried out to detect mutations in the MPO gene. Of approximately 40,000 individuals analyzed, seven partial and eight total MPO-deficient subjects were identified. The genetic characterization of the subjects showed the presence of three already,known mutations (c.752T>C, c.1705C>T, and c.1566_1579del14) and six novel mutations: four missense mutations (c.995C>T, c.1112A>G, c.1715T>G, and c.1927T>C), then a deletion of an adenine within exon 3 (c.325delA) and a mutation within the 3' splice site of intron 11 (c.2031-2A>C). The novel missense mutations cause the substitution of the residues p.A332V, p.D371G, p.L572W, and p.W643R, respectively, and the potential structural changes are discussed. The c.325delA deletion causes a shift of the reading frame with the occurrence of a premature stop codon within the propeptide. Then, considering the difficulty in obtaining bone marrow samples from MPO-deficient subjects to study MPO mRNA splicing in vivo, we set up an eukaryotic expression system to investigate how the c.2031-2A>C mutation alters the MPO pre-mRNA splicing. The activation of a cryptic 3' splice site located 109nt upstream of the authentic 3' splice site was observed. The 109nt-insertion causes a shift in the reading frame that should lead to the generation of an abnormal MPO precursor lacking the enzymatic activity. (C) 2004 Wiley-Liss, Inc.