Exacerbation of mild lung disorders to lethal pulmonary hypoplasia by a noncoding hypomorphic SNV in a lung-specific enhancer in trans to the frameshifting TBX4 variant.
Exacerbation of mild lung disorders to lethal pulmonary hypoplasia by a noncoding hypomorphic SNV in a lung-specific enhancer in trans to the frameshifting TBX4 variant.
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DOI：
10.1002/ajmg.a.62656
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发表时间：
2022-05
期刊：
影响因子：
--
通讯作者：
Stankiewicz P
中科院分区：
文献类型：
--
作者：
Yıldız Bölükbaşı E;Karolak JA;Szafranski P;Gambin T;Murik O;Zeevi DA;Altarescu G;Stankiewicz P
与TBX4相关的变异与多种疾病有关，包括肺动脉高压、坐骨神经足趾综合征(ICPPS)、新生儿致死性肺发育障碍(LLDDS)、心脏缺陷以及产前致死性后遗症合并盆腔和肺发育不良综合征。我们研究的目的是阐明一个带有TBX4截断变异体的三代家系中广泛可变的表型表达和不完全外显。除了外显子组和基因组测序分析外，还使用体外荧光素酶报告基因分析对肺特异性TBX4增强子内的候选非编码调节性SNV进行了功能测试。在轻度间质性肺疾病(1例)、毛细支气管炎闭塞症(1例)、复发性气胸(1例)、ICPPS(1例)、LLDD(2例)患者和正常对照(4例)中，发现了一个TBX4杂合性移码突变C.1115dup(p.Pro373 Serf*14)。在两名LLDD死亡新生儿中，我们发现了一个非编码SNV rs62069651-C，位于突变的TBX4等位基因的反式，在报告试验中使TBX4启动子的活性降低了63%。我们的发现为最近报道的复杂化合物遗传模型提供了功能证据，在该模型中，肺特异性增强子中的TBX4编码和反式非编码亚型变异都与LLDD有关。
Variants involving TBX4 are associated with a wide variety of disorders, including pulmonary arterial hypertension, ischiocoxopodopatellar syndrome (ICPPS), lethal lung developmental disorders (LLDDs) in neonates, heart defects, and prenatally lethal posterior amelia with pelvic and pulmonary hypoplasia syndrome. The objective of our study was to elucidate the wide variable phenotypic expressivity and incomplete penetrance in a three-generation family with a truncating variant in TBX4. In addition to exome and genome sequencing analyses, a candidate non-coding regulatory SNV within the lung-specific TBX4 enhancer was functionally tested using an in vitro luciferase reporter assay. A heterozygous frameshift variant c.1115dup (p.Pro373Serfs*14) in TBX4 was identified in patients with mild interstitial lung disease (1), bronchiolitis obliterans (1), recurrent pneumothorax (1), ICPPS (1), LLDD (2), and in unaffected individuals (4). In two deceased neonates with LLDD, we identified a non-coding SNV rs62069651-C located in trans to the mutated TBX4 allele that reduced the TBX4 promoter activity by 63% in the reporter assay. Our findings provide a functional evidence for the recently reported model of complex compound inheritance in which both TBX4 coding and in trans non-coding hypomorphic variants in the lung-specific enhancer of TBX4 contribute to LLDD.
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影响因子：
9.8
作者：
Coban-Akdemir, Zeynep;White, Janson J.;Carvalho, Claudia M. B.
通讯作者：
Carvalho, Claudia M. B.
影响因子：
2
作者：
Szafranski, Przemyslaw;Coban-Akdemir, Zeynep H.;Stankiewicz, Pawel
通讯作者：
Stankiewicz, Pawel
TBX6 无效变异和先天性脊柱侧凸中常见的低等位基因。
DOI：
10.1056/nejmoa1406829
发表时间：
2015-01-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Wu N;Ming X;Xiao J;Wu Z;Chen X;Shinawi M;Shen Y;Yu G;Liu J;Xie H;Gucev ZS;Liu S;Yang N;Al-Kateb H;Chen J;Zhang J;Hauser N;Zhang T;Tasic V;Liu P;Su X;Pan X;Liu C;Wang L;Shen J;Shen J;Chen Y;Zhang T;Zhang J;Choy KW;Wang J;Wang Q;Li S;Zhou W;Guo J;Wang Y;Zhang C;Zhao H;An Y;Zhao Y;Wang J;Liu Z;Zuo Y;Tian Y;Weng X;Sutton VR;Wang H;Ming Y;Kulkarni S;Zhong TP;Giampietro PF;Dunwoodie SL;Cheung SW;Zhang X;Jin L;Lupski JR;Qiu G;Zhang F
通讯作者：
Zhang F
影响因子：
4
作者：
Kerstjens-Frederikse WS;Bongers EM;Roofthooft MT;Leter EM;Douwes JM;Van Dijk A;Vonk-Noordegraaf A;Dijk-Bos KK;Hoefsloot LH;Hoendermis ES;Gille JJ;Sikkema-Raddatz B;Hofstra RM;Berger RM
通讯作者：
Berger RM
影响因子：
9.8
作者：
Karolak, Justyna A.;Vincent, Marie;Stankiewicz, Pawe
通讯作者：
Stankiewicz, Pawe