Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan.
Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan.
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DOI：
10.1016/s0021-9258(17)42244-7
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发表时间：
1994-01
期刊：
影响因子：
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通讯作者：
William;Nauseee;Susan Brigham;M. Cogley
中科院分区：
文献类型：
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作者：
William;Nauseee;Susan Brigham;M. Cogley
遗传性髓过氧化物酶缺乏症是一种常见的疾病，但其遗传基础尚不清楚。我们曾报道过MPO缺乏的中性粒细胞缺乏成熟MPO的酶和免疫化学证据，但有一个90 kDa的前体蛋白。因此，我们假设遗传性MPO缺陷反映了突变的初级翻译产物的加工缺陷。用BglII消化并用MPO的放射性标记cDNA探测的来自正常受试者的基因组DNA具有2.6 kb条带。以前，我们描述了存在一个异常的2.1 kb的片段BglII从大多数人与部分或完全MPO缺乏症。我们在这里描述负责的突变。在基因组序列的第8，089位核苷酸的外显子10中，胸苷取代胞嘧啶导致产生正常情况下不存在的BglII识别位点，并将正常的2.6-kb BglII片段转化为与MPO缺陷相关的2.1-kb片段。在氨基酸水平上，该突变将用色氨酸取代密码子569处的精氨酸。7例MPO完全缺乏症患者中有6例有这种突变。1例受试者为该突变的纯合子，而另外5例受试者为该位点的杂合子。第七位患者是唯一一位没有这种突变的完全缺陷受试者。因此，至少有两个突变和三种基因型可以产生MPO缺陷的表型。
Hereditary deficiency of myeloperoxidase (MPO) is a common disorder but its genetic basis is unknown. We have reported that neutrophils from individuals with MPO deficiency lack enzymatic and immunochemical evidence for mature MPO but have a 90-kDa precursor protein. We have thus hypothesized that hereditary MPO deficiency reflects a defect in processing of a mutated primary translation product. Genomic DNA's from normal subjects digested with BglII and probed with radiolabeled cDNA for MPO have a 2.6-kilobase (kb) band. Previously we described the presence of an aberrant 2.1-kb fragment in BglII digests from most individuals with either partial or complete MPO deficiency. We describe here the responsible mutation. The substitution of thymidine for cytosine in exon 10 at nucleotide 8,089 of the genomic sequence results in generation of a recognition site for BglII not present normally and converts the normal 2.6-kb BglII fragment to the 2.1-kb fragment associated with MPO deficiency. At the amino acid level this mutation would replace arginine at codon 569 with tryptophan. Six of seven patients with complete MPO deficiency had this mutation. One subject was homozygous for this mutation whereas five others were heterozygous at this locus. The seventh patient was the only completely deficient subject without this mutation. Thus, at least two mutations and three genotypes can produce the phenotype of MPO deficiency.