Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease
Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease
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DOI：
10.1093/hmg/ddg363
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发表时间：
2003-12-15
影响因子：
3.5
通讯作者：
Noris, M
中科院分区：
文献类型：
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作者：
Caprioli, J;Castelletti, F;Noris, M
非志贺毒素相关和志贺阴性溶血性尿毒综合征（D-HUS）中有报道存在补体因子H（HF 1）基因突变。我们分析了101例HUS患者、32例血栓性血小板减少性紫癜（TTP）患者和106例对照者的完整HF 1，以评估HF 1突变频率、突变和非突变携带者的临床结局以及HF 1多态性在HUS易感性中的作用。我们在33例HUS患者中发现了17个HF 1突变（16个杂合子，1个纯合子）。13个突变位于外显子XXII和XXIII。TTP患者均未携带HF 1突变。突变携带者比非携带者发病更早，死亡率更高。在HF 1突变的患者中，肾移植总是因疾病复发而失败，而在非突变患者中，一半的移植物在1年后仍有功能。3个HF 1多态性变体与D-HUS强相关：-257T（启动子区）、2089 G（外显子XIV，沉默）和2881 T（963 Asp，SCR 16）。这种关联在没有HF 1突变的患者中更强。两种或三种疾病相关的变异导致HUS的风险高于单一变异。对突变患者亲属的分析显示，突变率为50%。在5/9个家庭中，先证者从父母一方遗传了突变，从另一方遗传了两种疾病相关的变异，而未受影响的携带者则遗传了保护性变异。总之，HF 1突变在D-HUS患者中很常见（24%）。常见的HF 1多态性可能有助于D-HUS表现在受试者和没有HF 1突变。
Mutations in complement factor H (HF1) gene have been reported in non-Shiga toxin-associated and diarrhoea-negative haemolytic uraemic syndrome (D-HUS). We analysed the complete HF1 in 101 patients with HUS, in 32 with thrombotic thrombocytopenic purpura (TTP) and in 106 controls to evaluate the frequency of HF1 mutations, the clinical outcome in mutation and non-mutation carriers and the role of HF1 polymorphisms in the predisposition to HUS. We found 17 HF1 mutations (16 heterozygous, one homozygous) in 33 HUS patients. Thirteen mutations were located in exons XXII and XXIII. No TTP patient carried HF1 mutations. The disease manifested earlier and the mortality rate was higher in mutation carriers than in non-carriers. Kidney transplants invariably failed for disease recurrences in patients with HF1 mutations, while in non-mutated patients half of the grafts were functioning after 1 year. Three HF1 polymorphic variants were strongly associated with D-HUS: -257T (promoter region), 2089G (exonXIV, silent) and 2881T (963Asp, SCR16). The association was stronger in patients without HF1 mutations. Two or three disease-associated variants led to a higher risk of HUS than a single one. Analysis of available relatives of mutated patients revealed a penetrance of 50%. In 5/9 families the proband inherited the mutation from one parent and two disease-associated variants from the other, while unaffected carriers inherited the protective variants. In conclusion HF1 mutations are frequent in patients with D-HUS (24%). Common polymorphisms of HF1 may contribute to D-HUS manifestation in subjects with and without HF1 mutations.