Variant-specific quantification of factor H in plasma identifies null alleles associated with atypical hemolytic uremic syndrome.
Variant-specific quantification of factor H in plasma identifies null alleles associated with atypical hemolytic uremic syndrome.
复制标题
DOI：
10.1038/ki.2010.275
复制
发表时间：
2010-10
影响因子：
19.6
通讯作者：
Morgan, Bryan P.
中科院分区：
文献类型：
--
作者：
Hakobyan, Svetlana;Tortajada, Agustin;Harris, Claire L.;de Cordoba, Santiago R.;Morgan, Bryan P.
在超过50%的病例中，非典型溶血性尿毒症综合征（aHUS）与补体替代途径缺陷相关。因子H （fH）突变是最常见的，通常是影响补体表面调节的点突变，有时是杂合性的零突变。后者很难识别；虽然持续的低血浆fH浓度具有启发性，但需要明确的证据证明突变序列在体外不表达。在这里，使用区分和单独量化常见fH- y402h多态性变异的新试剂和分析方法来鉴定导致全长fH低表达或不表达（“零”）的CFH基因等位基因，但在这些分析中也检测到替代剪接产物FHL-1的正常或增加表达。他们在aHUS队列中发现了三个Y402H杂合子，fH-H402低或缺失，但FHL-1水平正常或升高。杂合子的新突变解释了两个病例的零表型，其中一个经家庭研究证实。在第三个病例中，家族研究表明，Y等位基因上存在已知的突变；虽然数据显示fH/FHL-1剪接改变，但未发现H等位基因表达减少的原因。在每个家庭中，fH“低表达”或“空”等位基因的遗传与aHUS密切相关。这些检测提供了一种快速的方法来识别aHUS中fH表达缺陷，而无需诉诸基因测序或表达分析。
Atypical hemolytic uremic syndrome (aHUS) associates with complement alternative pathway defects in over 50% of cases. Mutations in factor H (fH) are most common, usually point mutations affecting complement surface regulation and sometimes null mutations in heterozygosity. The latter are difficult to identify; although consistently low plasma fH concentration is suggestive, definitive proof has required the demonstration that the mutant sequence does not express in vitro. Here, novel reagents and assays that distinguish and individually quantify the common fH-Y402H polymorphic variants were used to identify alleles of the CFH gene resulting in low or no (‘null’) expression of full-length fH, but normal or increased expression of the alternative splice product FHL-1, also detected in these assays. Their use in an aHUS cohort identified three Y402H heterozygotes with low or absent fH-H402 but normal or increased FHL-1 levels. Novel mutations in heterozygosis explained the null phenotype in two cases, confirmed by family studies in one. In the third case, family studies showed that a known mutation was present on the Y allele; the cause of the reduced expression of H allele was not found, although data suggested altered fH/FHL-1 splicing. In each family, inheritance of “low expression” or “null” alleles for fH strongly associated with aHUS. These assays provide a rapid means to identify fH expression defects in aHUS without resorting to gene sequencing or expression analysis.
登录
查看更多内容
影响因子：
1.2
作者：
Kind, T;Levy, J;Kane, SA
通讯作者：
Kane, SA
影响因子：
11.8
作者：
Becker, S;Fusco, G;Feinberg, J
通讯作者：
Feinberg, J
影响因子：
13.2
作者：
Constantinescu, AR;Bitzan, M;Trachtman, H
通讯作者：
Trachtman, H
影响因子：
4.8
作者：
Ault, BH;Schmidt, BZ;Colten, HR
通讯作者：
Colten, HR
影响因子：
56.9
作者：
Edwards, AO;Ritter, R;Farrer, LA
通讯作者：
Farrer, LA