PDF(Pubmed)
Abstract：
Rationale: Despite the increased recognition of TBX4 (T-BOX transcription factor 4)-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights. Objectives: To compile and functionally characterize all TBX4 variants reported to date and undertake a comprehensive genotype-phenotype analysis. Methods: We assembled a multicenter cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with patients with PAH with BMPR2 (Bone Morphogenetic Protein Receptor type 2) causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the National Institute for Health Research BioResource-Rare Diseases. Measurements and Main Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared with loss-of-function effects (P = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (P = 0.005) and increased incidence of interstitial lung disease (P = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (P = 0.022), although age had a significant effect in the hazard model (P = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (P < 0.001) and had worse baseline lung function (FEV1, FVC) (P = 0.009) than the BMPR2 and no identified causal variant groups. Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain of function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.
摘要：
原理：尽管TBX4（T-BOX转录因子4）相关肺动脉高压（PAH）的识别增加，缺乏基因型-表型关联,可能提供重要见解.目标：编译和功能表征所有TBX4变异迄今报道，并进行全面的基因型-表型分析。方法：我们组装了137例单等位基因TBX4变体患者的多中心队列，并使用包含T-BOX结合基序的新型荧光素酶报告基因测定法评估了错义变异的致病性（n=42）。我们寻求基因型-表型相关性，并与患有BMPR2（骨形态发生蛋白受体2型）因果变异（n=162）或未鉴定的PAH相关基因变异（n=741）的PAH患者进行了比较分析。通过美国国立卫生研究生物资源-罕见疾病研究所进行基因分型。测量和主要结果：TBX4错义变异的功能评估导致与功能丧失效应相比，在诊断肺部疾病时与年龄相关的功能获得效应的新发现（P=0.038）。位于T-BOX和核定位域的变异与早期表现（P=0.005）和间质性肺病发病率增加（P=0.003）相关。T-BOX组的无事件生存期（死亡或移植）较短（P=0.022），尽管年龄在风险模型中有显著影响(P=0.0461).TBX4变异的携带者在较年轻的年龄(P<0.001)被诊断,并且具有比BMPR2更差的基线肺功能(FEV1,FVC)(P=0.009),并且没有确定的因果变异组。结论：我们证明TBX4综合征不是严格的单倍体功能不全的结果，也可能是由功能获得引起的。TBX4在肺部疾病中的多效性作用可能部分由位于关键蛋白质结构域中的致病性突变的差异作用来解释。
