Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4α mutations in a large European collection
Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4α mutations in a large European collection
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DOI：
10.1007/s00125-005-1738-y
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发表时间：
2005-05-01
期刊：
影响因子：
8.2
通讯作者：
Hattersley, AT
中科院分区：
文献类型：
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作者：
Pearson, ER;Pruhova, S;Hattersley, AT
目的/假设：与肝细胞核因子4成比例的转录因子（与HNF-4成比例）基因的杂合突变被认为是MODY的罕见原因，迄今为止仅报告了14种突变。表型的描述仅限于单个家族。我们调查了一个大型欧洲高加索人集合中HNF-4 α突变的遗传学和表型。方法：对48例MODY先证者进行HNF-4 α测序，选择HNF-1 α MODY表型，但HNF-1 α突变阴性。我们比较了54例HNF-4 α突变携带者和32例来自10个新发现或先前描述的家族的家族对照的临床特征和生化指标。结果：在14/48例（29%）HNF-1 α突变阴性的先证者中发现HNF-4 α突变。发现的突变包括7个新突变：S34 X、D206 Y、E276 D、L332 P、I314 F、L332 insCTG和IVS 5 nt +1G > A。I314 F是第一个报道的HNF-4a的新突变。诊断的平均年龄为22.9岁，临床上经常有对磺脲类药物敏感的证据。与对照受试者相比，糖尿病突变携带者的β细胞功能降低，但胰岛素敏感性不降低（β细胞功能的稳态模型评估为29%p < 0.001 vs对照）。与对照组相比，HNF-4 α突变与较低的载脂蛋白A2（p=0.001）、A1（p=0.04）和总HDL-胆固醇（p=0.02）相关。然而，与以前的一些报告相反，甘油三酯和载脂蛋白C3水平正常。结论/解释：当在严格定义的MODY家族中没有发现HNF-1 α突变时，HNF-4 α突变是常见的。HNF-4 α临床表型和β细胞功能障碍与HNF-1 α MODY相似，并与载脂蛋白A2水平降低相关。我们建议，HNF-4 α的测序应在HNF-1 α MODY的临床特征的患者中进行，在HNF-1 α中未发现突变。
Aims/hypothesis: Heterozygous mutations in the gene of the transcription factor hepatocyte nuclear factor 4 proportional to (HNF-4 proportional to) are considered a rare cause of MODY with only 14 mutations reported to date. The description of the phenotype is limited to single families. We investigated the genetics and phenotype of HNF-4 alpha mutations in a large European Caucasian collection. Methods: HNF-4 alpha was sequenced in 48 MODY probands, selected for a phenotype of HNF-1 alpha MODY but negative for HNF-1 alpha mutations. Clinical characteristics and biochemistry were compared between 54 HNF-4 alpha mutation carriers and 32 familial controls from ten newly detected or previously described families. Results: Mutations in HNF-4 alpha were found in 14/48 (29%) probands negative for HNF-1 alpha mutations. The mutations found included seven novel mutations: S34X, D206Y, E276D, L332P, I314F, L332insCTG and IVS5nt+1G > A. I314F is the first reported de novo HNF-4a mutation. The average age of diagnosis was 22.9 years with frequent clinical evidence of sensitivity to sulphonylureas. Beta cell function, but not insulin sensitivity, was reduced in diabetic mutation carriers compared to control subjects ( homeostasis model assessment of beta cell function 29% p < 0.001 vs controls). HNF-4 alpha mutations were associated with lower apolipoprotein A2 (p=0.001), A1 (p=0.04) and total HDL-cholesterol (p=0.02) than in control subjects. However, in contrast to some previous reports, levels of triglycerides and apolipoprotein C3 were normal. Conclusions/interpretation: HNF-4 alpha mutations are common when no HNF-1 alpha mutation is found in strictly defined MODY families. The HNF-4 alpha clinical phenotype and beta cell dysfunction are similar to HNF-1 alpha MODY and are associated with reduced apolipoprotein A2 levels. We suggest that sequencing of HNF-4 alpha should be performed in patients with clinical characteristics of HNF-1 alpha MODY in whom mutations in HNF-1 alpha are not found.