Park Jong Eun, Park Jin Seok, Jang Shin Yi, Park Seok Hee, Kim Jong-Won, Ki Chang-Seok, Kim Duk-Kyung
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
Mol Genet Genomic Med. 2019 May;7(5):e620. doi: 10.1002/mgg3.620. Epub 2019 Mar 8.
Bicuspid aortic valve (BAV) is the most common congenital heart defect with a prevalence of 1%-2% in the general population. NOTCH1, SMAD6, and GATA5 are associated with BAV in humans, but few cases have been reported that did not involve NOTCH1. Here, we identified novel in-frame variants in SMAD6 (c.1168_1173dup; p.Gly390_Ile391dup) in a BAV patient, who presented with dilatation of the ascending aorta and severe calcification of the aortic valve.
Twenty BAV associated genes were screened by exome sequencing. Functional effects of SMAD6 variant were investigated using bone morphogenetic protein (BMP) signaling assays through in vitro functional study.
Exome sequencing revealed he had novel in-frame variants in the SMAD6 gene (c.1168_1173dup; p.Gly390_Ile391dup). SMAD6 is known to be an inhibitory protein in the BMP signaling pathway. In vitro functional study of the p.Gly390_Ile391dup variant revealed impaired inhibition of BMP signaling and BMP-induced alkaline phosphatase activity.
In conclusion, we identified a novel SMAD6 variant causing a severely calcified BAV and TAA, which contributes to our understanding of the clinical and genetic background of SMAD6-related BAV.
二叶式主动脉瓣（BAV）是最常见的先天性心脏缺陷，在普通人群中的患病率为1%-2%。NOTCH1、SMAD6和GATA5与人类的BAV相关，但很少有不涉及NOTCH1的病例报道。在此，我们在一名BAV患者中鉴定出SMAD6的新型框内变异（c.1168_1173dup；p.Gly390_Ile391dup），该患者表现为升主动脉扩张和主动脉瓣严重钙化。
通过外显子组测序筛选20个与BAV相关的基因。通过体外功能研究，使用骨形态发生蛋白（BMP）信号检测法研究SMAD6变异的功能效应。
外显子组测序显示他在SMAD6基因中有新型框内变异（c.1168_1173dup；p.Gly390_Ile391dup）。已知SMAD6是BMP信号通路中的一种抑制蛋白。对p.Gly390_Ile391dup变异的体外功能研究显示，其对BMP信号和BMP诱导的碱性磷酸酶活性的抑制作用受损。
总之，我们鉴定出一种导致严重钙化的BAV和胸主动脉瘤（TAA）的新型SMAD6变异，这有助于我们了解与SMAD6相关的BAV的临床和遗传背景。
