A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy.
A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy.
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DOI：
10.1371/journal.pone.0049083
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Baratz KH
中科院分区：
文献类型：
--
作者：
Wieben ED;Aleff RA;Tosakulwong N;Butz ML;Highsmith WE;Edwards AO;Baratz KH
Fuchs角膜内皮营养不良（FECD）是一种常见的家族性角膜内皮疾病，是角膜移植的主要适应症。转录因子4（TCF 4）基因的变异已被确定为该疾病的主要贡献者。我们在一项3阶段发现/复制/验证研究中，通过确定66名患有严重FECD的受影响参与者和63名正常角膜参与者的重复长度，检测了TCF 4中内含子TGC三核苷酸重复与FECD之间的关联。使用TGC重复序列侧翼的PCR引物扩增白细胞来源的基因组DNA。通过直接测序、短串联重复序列（STR）分析和Southern印迹法测定重复序列长度。使用基因组Southern印迹来评估仅通过STR分析鉴定出单个等位基因的样品。收集3组研究的数据，79%的FECD病例和3%的正常对照病例中存在TGC重复长度> 50（p <0.001）。在这些病例中，66例受试者中有52例（79%）具有> 50个TGC重复，13例（20%）具有<40个重复，1例（2%）具有中等重复长度。相比之下，63名未受影响的对照受试者中只有2名（3%）具有> 50个重复，60名（95%）具有<40个重复，1名（2%）具有中等重复长度。4例FECD重复长度大于1000。在该患者队列中，> 50个TGC重复鉴定FECD的灵敏度和特异性分别为79%和96%，扩展的TGC重复对FECD病例的特异性高于先前鉴定的高度相关的单核苷酸多态性rs613872（特异性= 79%）。 TCF 4中的TGC三核苷酸重复扩增与FECD强烈相关，并且重复长度> 50对该疾病具有高度特异性。这种关联表明三核苷酸扩增可能在大多数FECD病例中起致病作用，并且是疾病风险的预测因子。
Fuchs endothelial corneal dystrophy (FECD) is a common, familial disease of the corneal endothelium and is the leading indication for corneal transplantation. Variation in the transcription factor 4 (TCF4) gene has been identified as a major contributor to the disease. We tested for an association between an intronic TGC trinucleotide repeat in TCF4 and FECD by determining repeat length in 66 affected participants with severe FECD and 63 participants with normal corneas in a 3-stage discovery/replication/validation study. PCR primers flanking the TGC repeat were used to amplify leukocyte-derived genomic DNA. Repeat length was determined by direct sequencing, short tandem repeat (STR) assay and Southern blotting. Genomic Southern blots were used to evaluate samples for which only a single allele was identified by STR analysis. Compiling data for 3 arms of the study, a TGC repeat length >50 was present in 79% of FECD cases and in 3% of normal controls cases (p<0.001). Among cases, 52 of 66 (79%) subjects had >50 TGC repeats, 13 (20%) had <40 repeats and 1 (2%) had an intermediate repeat length. In comparison, only 2 of 63 (3%) unaffected control subjects had >50 repeats, 60 (95%) had <40 repeats and 1 (2%) had an intermediate repeat length. The repeat length was greater than 1000 in 4 FECD cases. The sensitivity and specificity of >50 TGC repeats identifying FECD in this patient cohort was 79% and 96%, respectively Expanded TGC repeat was more specific for FECD cases than the previously identified, highly associated, single nucleotide polymorphism, rs613872 (specificity = 79%). The TGC trinucleotide repeat expansion in TCF4 is strongly associated with FECD, and a repeat length >50 is highly specific for the disease This association suggests that trinucleotide expansion may play a pathogenic role in the majority of FECD cases and is a predictor of disease risk.
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