Duchemin J, Gandrille S, Borgel D, Feurgard P, Alhenc-Gelas M, Matheron C, Dreyfus M, Dupuy E, Juhan-Vague I, Aiach M
Unité INSERM 428, UFR des Sciences Pharmaceutiques et Biologiques, Université Paris V, France.
Blood. 1995 Nov 1;86(9):3436-43.
A Ser 460 to Pro mutation of protein S (PS), involving a T to C transition in exon XIII of the protein S alpha (PROS1) gene and known as the Heerlen polymorphism, was found in 16 of 85 symptomatic patients with PS deficiency (18.8%) and only 1 of 113 healthy subjects (0.8%). Another frequent polymorphism was described in exon XV of the PROS1 gene, in the codon for Pro 626 (CCA/CCG). We found that Heerlen polymorphism was associated with allele CCA and not with allele CCG, suggesting a probable transmission by a common ancestor. Most subjects bearing the Ser 460 to Pro mutation were deficient in free PS, but had normal total PS levels. Normal levels of the C4b-binding protein (C4b-BP) isoform containing a beta chain (C4b-BP beta +) ruled out increased C4b-BP beta + as a cause of the free-PS deficiency. The binding curves of the mutated (Heerlen) PS on C4b-BP immobilized on microplates were biphasic, suggesting that one molecule of C4b-BP can bind two molecules of Heerlen PS. Because normal PS binds to C4b-BP with 1:1 stoichiometry, this may explain the free-PS deficiency observed in patients carrying the Ser 460 to Pro mutation.
在85例有症状的蛋白S（PS）缺乏患者中，有16例（18.8%）发现蛋白S（PS）的丝氨酸460突变为脯氨酸，该突变涉及蛋白Sα（PROS1）基因第XIII外显子中的T到C转换，即所谓的海尔伦多态性，而在113名健康受试者中仅1例（0.8%）发现该突变。在PROS1基因的第XV外显子中，脯氨酸626（CCA/CCG）密码子处描述了另一种常见的多态性。我们发现海尔伦多态性与CCA等位基因相关，而与CCG等位基因无关，这表明可能是由一个共同祖先遗传而来。大多数携带丝氨酸460突变为脯氨酸的受试者游离PS缺乏，但总PS水平正常。含有β链的C4b结合蛋白（C4b-BP）异构体（C4b-BPβ+）水平正常，排除了C4b-BPβ+增加是游离PS缺乏的原因。固定在微孔板上的C4b-BP上的突变型（海尔伦）PS的结合曲线是双相的，这表明一个C4b-BP分子可以结合两个海尔伦PS分子。由于正常PS与C4b-BP以1:1的化学计量比结合，这可能解释了携带丝氨酸460突变为脯氨酸的患者中观察到的游离PS缺乏现象。
