McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Howard Hughes Medical Institute, Baltimore, MD, USA.
Nat Genet. 2019 Jan;51(1):42-50. doi: 10.1038/s41588-018-0265-y. Epub 2018 Nov 19.
Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2%) that frequently presents with ascending aortic aneurysm (AscAA). BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for ≤1% of nonsyndromic BAV cases with and without AscAA, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.
二叶式主动脉瓣（BAV）是一种常见的先天性心脏缺陷（人群发病率为 1-2%），常伴有升主动脉瘤（AscAA）。BAV/AscAA 呈常染色体显性遗传，不完全外显且男性居多。已知 ≤1%的非综合征性 BAV 病例伴有或不伴有 AscAA 存在致病基因突变（例如 NOTCH1、SMAD6），这阻碍了对发病机制的深入了解和治疗策略的发展。在这里，我们报道了 ROBO4 变异的鉴定（其编码已知有助于内皮功能的因子），该变异在两个家族中与疾病分离。与对照组相比，ROBO4 靶向测序显示 BAV/AscAA 先证者中罕见变异富集。内皮细胞系中 ROBO4 或突变 ROBO4 的靶向沉默导致屏障功能受损，以及提示内皮-间充质转化的合成谱。这与患者和 ROBO4 缺陷的动物模型中的 BAV/AscAA 相关发现一致。这些数据确定了这种常见人类疾病表型的新的内皮病因。
