Systematic survey of variants in TBX1 in non-syndromic tetralogy of Fallot identifies a novel 57 base pair deletion that reduces transcriptional activity but finds no evidence for association with common variants
Systematic survey of variants in TBX1 in non-syndromic tetralogy of Fallot identifies a novel 57 base pair deletion that reduces transcriptional activity but finds no evidence for association with common variants
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DOI：
10.1136/hrt.2010.200121
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发表时间：
2010-10-01
期刊：
影响因子：
5.7
通讯作者：
Goodship, Judith A.
中科院分区：
文献类型：
--
作者：
Griffin, Helen R.;Toepf, Ana;Goodship, Judith A.
研究背景法洛四联症（Tetralogy of Fallot，TOF）是一种常见的心脏转录因子TBX1基因缺失的疾病。目的探讨常见和罕见TBX1基因变异在TOF发病中的作用。通过对20个单倍型标记的SNP进行基因分型来研究常见的TBX1变体，这些SNP捕获了该位点存在的所有常见变异。应用UNPHASED程序对93例非综合征性TOF患者的TBX1基因外显子序列进行分析。对356例TOF患者及其父母和健康对照者进行单核苷酸多态性分析。其中一种变体，在第三外显子中的框内57个碱基对缺失，去除了19个进化上保守的残基，在双荧光素酶测定中使转录活性降低了40%（p=0.008）。蛋白表达研究表明，该突变影响TBX1蛋白的稳定性。校正后的多重比较，常见的遗传变异和TOF的易感性之间没有显着的关联被发现。结论本研究表明，罕见的TBX1变异的功能后果是存在于一小部分的非综合征性TOF。
Background Tetralogy of Fallot (TOF) is common in individuals with hemizygous deletions of chromosome 22q11.2 that remove the cardiac transcription factor TBX1.Objective To assess the contribution of common and rare TBX1 genetic variants to TOF.Design Rare TBX1 variants were sought by resequencing coding exons and splice-site boundaries. Common TBX1 variants were investigated by genotyping 20 haplotype-tagging SNPs capturing all the common variations present at the locus. Association analysis was performed using the program UNPHASED.Patients TBX1 exons were sequenced in 93 patients with non-syndromic TOF. Single nucleotide polymorphism analysis was performed in 356 patients with TOF, their parents and healthy controls.Results Three novel variants not present in 1000 chromosomes from healthy ethnically matched controls were identified. One of these variants, an in-frame 57 base-pair deletion in the third exon which removed 19 evolutionarily conserved residues, decreased transcriptional activity by 40% in a dual luciferase assay (p=0.008). Protein expression studies demonstrated that this mutation affected TBX1 protein stability. After correction for multiple comparisons, no significant associations between common genetic variants and TOF susceptibility were found.Conclusion This study demonstrates that rare TBX1 variants with functional consequences are present in a small proportion of non-syndromic TOF.