Molecular characterization of properdin deficiency type III: dysfunction produced by a single point mutation in exon 9 of the structural gene causing a tyrosine to aspartic acid interchange.
Molecular characterization of properdin deficiency type III: dysfunction produced by a single point mutation in exon 9 of the structural gene causing a tyrosine to aspartic acid interchange.
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III 型备解素缺乏症的分子特征：结构基因外显子 9 中的单点突变导致酪氨酸与天冬氨酸互换而产生功能障碍。
DOI：
10.4049/jimmunol.157.8.3666
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发表时间：
1996
影响因子：
4.4
通讯作者：
L. Truedsson
中科院分区：
文献类型：
--
作者：
G. N. Fredrikson;J. Westberg;E. Kuijper;C. Tijssen;A. Sjöholm;Mathias Uhlén;L. Truedsson
遗传性备解素缺乏症是一种X连锁隐性遗传疾病，临床表现为对脑膜炎球菌病的易感性。备解素缺乏的特征在于完全缺乏（I型）、非常低水平的存在（II型）或在血清中存在功能障碍的备解素蛋白，如在一个荷兰家族中发现的（III型）。为了更好地了解分子水平上的功能失调蛋白，通过直接基因组测序分析了来自荷兰家族三名成员的样本。测定了包括10个外显子和9个内含子，约6500个碱基的全基因序列。发现功能障碍的备解素是由外显子9中的单个T至G突变引起的，其引起在位置387处的酪氨酸被天冬氨酸残基取代。这种亲水性氨基酸的变化影响备解素分子的功能，尽管功能失调的备解素分子的寡聚化与正常备解素的寡聚化相似。在与C3b和备解素在血清中的结合研究中，没有备解素沉积与III型缺陷的血清检测。不同的十肽的抑制研究揭示了不同的抑制序列，也表明备解素的一部分含有III型突变不直接参与结合C3b。该突变最有可能导致构象变化，通过影响其与C3b的结合而使备解素分子功能障碍。
Inherited properdin deficiency is an X-linked recessive disorder clinically manifested by susceptibility to meningococcal disease. Deficiency of properdin is characterized by complete absence (type I), very low level presence (type II), or the presence of a dysfunctional properdin protein in serum as found in one Dutch family (type III). To better understand the dysfunctional protein on the molecular level, samples from three members of the Dutch family were analyzed by direct genomic sequencing. The sequence of the complete gene, including 10 exons and 9 introns, covering about 6500 bases was determined. The dysfunctional properdin was found to be caused by a single T to G mutation in exon 9, which gives rise to a substitution of a tyrosine by an aspartic acid residue at position 387. This change to a hydrophilic amino acid affects the function of the properdin molecule, although the oligomerization of dysfunctional properdin molecules was similar to that of normal properdin. In binding studies with C3b and properdin in serum, no properdin deposition was detected with the type III deficient serum. Inhibition studies with different decapeptides revealed distinct inhibitory sequences, and indicated also that the part of properdin containing the type III mutation was not directly involved in the binding to C3b. The mutation most likely causes conformational changes that make the properdin molecule dysfunctional by affecting its binding to C3b.