Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot.
Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot.
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DOI：
10.1038/s41436-021-01212-y
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Bezzina CR
中科院分区：
文献类型：
--
作者：
Škorić-Milosavljević D;Lahrouchi N;Bosada FM;Dombrowsky G;Williams SG;Lesurf R;Tjong FVY;Walsh R;El Bouchikhi I;Breckpot J;Audain E;Ilgun A;Beekman L;Ratbi I;Strong A;Muenke M;Heide S;Muir AM;Hababa M;Cross L;Zhou D;Pastinen T;German Competence Network for Congenital Heart Defects;Zackai E;Atmani S;Ouldim K;Adadi N;Steindl K;Rauch A;Brook D;Wilsdon A;Kuipers I;Blom NA;Mulder BJ;Mefford HC;Keren B;Joset P;Kruszka P;Thiffault I;Sheppard SE;Roberts A;Lodder EM;Keavney BD;Clur SB;Mital S;Hitz MP;Christoffels VM;Postma AV;Bezzina CR
编码血管内皮生长因子受体2(VEGFR2)的KDR基因突变在法洛四联症(TOF)患者中已有报道。然而，它们在疾病因果关系和发病机制中的作用尚不清楚。我们在一个TOF家族性病例中进行了外显子组测序，并进行了大规模的遗传学研究，包括负荷测试、1,500名TOF患者。我们研究了以基因为靶点的小鼠，并进行了基于细胞的分析，以探索KDR基因变异在TOF病因学中的作用。在一个受TOF影响的有两个兄弟姐妹的家庭中，外显子组测序发现了KDR的双等位错义变异。在基因敲除小鼠和HEK 293T细胞中的研究证实，当一种变异发生在纯合状态时，胚胎死亡，并且两种变异的VEGFR2磷酸化显著降低。对1,569名欧洲血统的TOF患者进行了罕见的变异负荷分析，发现TOF患者的蛋白质截断变体(PTV)比对照组(P = 7 × 10-11)丰富了46倍。罕见的KDR变异体，特别是PTV，与TOF密切相关，可能存在不同的遗传模式。在遗传学和体内、体外功能分析的支持下，我们提出VEGFR2功能丧失是TOF发病机制之一。
Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear. We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF. Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10-11). Rare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF.
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影响因子：
16.6
作者：
Gräf S;Haimel M;Bleda M;Hadinnapola C;Southgate L;Li W;Hodgson J;Liu B;Salmon RM;Southwood M;Machado RD;Martin JM;Treacy CM;Yates K;Daugherty LC;Shamardina O;Whitehorn D;Holden S;Aldred M;Bogaard HJ;Church C;Coghlan G;Condliffe R;Corris PA;Danesino C;Eyries M;Gall H;Ghio S;Ghofrani HA;Gibbs JSR;Girerd B;Houweling AC;Howard L;Humbert M;Kiely DG;Kovacs G;MacKenzie Ross RV;Moledina S;Montani D;Newnham M;Olschewski A;Olschewski H;Peacock AJ;Pepke-Zaba J;Prokopenko I;Rhodes CJ;Scelsi L;Seeger W;Soubrier F;Stein DF;Suntharalingam J;Swietlik EM;Toshner MR;van Heel DA;Vonk Noordegraaf A;Waisfisz Q;Wharton J;Wort SJ;Ouwehand WH;Soranzo N;Lawrie A;Upton PD;Wilkins MR;Trembath RC;Morrell NW
通讯作者：
Morrell NW
影响因子：
4.8
作者：
Kroll, J;Waltenberger, J
通讯作者：
Waltenberger, J
影响因子：
20.1
作者：
Krenz, M;Yutzey, KE;Robbins, J
通讯作者：
Robbins, J
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
0.7
作者：
Egbe A;Lee S;Ho D;Uppu S;Srivastava S
通讯作者：
Srivastava S