Phosphorylated proteome analysis of a novel germline ABL1 mutation causing an autosomal dominant syndrome with ventricular septal defect
Phosphorylated proteome analysis of a novel germline ABL1 mutation causing an autosomal dominant syndrome with ventricular septal defect
复制标题
导致伴有室间隔缺损的常染色体显性遗传综合征的新型种系 ABL1 突变的磷酸化蛋白质组分析
DOI：
10.1016/j.ijcard.2020.10.032
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发表时间：
2021
影响因子：
3.5
通讯作者：
Kato Taichi
中科院分区：
文献类型：
--
作者：
Yamamoto Hidenori;Hayano Satoshi;Okuno Yusuke;Onoda Atsuto;Kato Kohji;Nagai Noriko;Fukasawa Yoshie;Saitoh Shinji;Takahashi Yoshiyuki;Kato Taichi
研究背景：胚系ABL1基因功能获得性突变导致包括先天性心脏病在内的综合征。然而，这种综合征的分子机制仍然未知。在本研究中，我们发现了一个新的ABL1基因突变的日本家庭与室间隔缺损，手指挛缩，皮肤异常和未能茁壮成长，并探讨这些表型的分子机制。方法和结果全外显子组测序的几个家庭成员揭示了一个新的突变（c.1522A> C，p.I508L），并且在所有成员中证实了与临床表现的完全共分离。将野生型和突变型ABL 1转染人胚肾293细胞进行功能分析。Western blotting证实，ABL1的底物STAT5的酪氨酸磷酸化增强，新突变被证明是功能获得性突变。由于ABL1中的这种新突变增强了酪氨酸激酶活性，磷酸化蛋白质组分析被用来阐明分子病理学。蛋白质组学分析表明，磷酸化的蛋白质，如UFD 1，AXIN 1，ATRX，这可能是参与的表型，增强在突变group.ConclusionsThe发病的先天性心脏病与此综合征似乎涉及的机制所造成的UFD 1共同22q.11.2缺失综合征。另一方面，AXIN1和ATRX可能在阐明其他表型的机制方面很重要，例如手指挛缩和发育不良。这些假设的验证将导致进一步了解的病理生理和治疗方法的发展。
BackgroundA gain-of-function mutation in germlineABL1causes a syndrome including congenital heart defects. However, the molecular mechanisms of this syndrome remain unknown. In this study, we found a novelABL1mutation in a Japanese family with ventricular septal defect, finger contracture, skin abnormalities and failure to thrive, and the molecular mechanisms of these phenotypes were investigated.Methods and resultsWhole-exome sequencing on several family members revealed a novel mutation (c.1522A > C, p.I508L) in the tyrosine kinase domain ofABL1, and complete co-segregation with clinical presentations was confirmed in all members. Wild-type and mutantABL1were transfected into human embryonic kidney 293 cells for functional analysis. Western blotting confirmed that tyrosine phosphorylation in STAT5, a substrate of ABL1, was enhanced, and the novel mutation was proved to be a gain-of-function mutation. Since this novel mutation inABL1enhances tyrosine kinase activity, phosphorylated proteome analysis was used to elucidate the molecular pathology. The proteome analysis showed that phosphorylation in proteins such as UFD1, AXIN1, ATRX, which may be involved in the phenotypes, was enhanced in the mutant group.ConclusionsThe onset of congenital heart defects associated with this syndrome appears to involve a mechanism caused by UFD1 common to 22q.11.2 deletion syndrome. On the other hand, AXIN1 and ATRX may be important in elucidating the mechanisms of other phenotypes, such as finger contracture and failure to thrive. Verification of these hypotheses would lead to further understanding of the pathophysiology and the development of treatment methods.