Vascular anomalies (VAs), comprising wide subtypes of tumors and malformations, are often caused by variants in multiple tyrosine kinase (TK) receptor signaling pathways including TIE2, PIK3CA and GNAQ/11. Yet, a portion of individuals with clinical features of VA do not have variants in these genes, suggesting that there are undiscovered pathogenic factors underlying these patients and possibly with overlapping phenotypes. Here, we identified one rare non-synonymous variant (c.968A > G) in the seventh exon of GPAA1 (Glycosylphosphatidylinositol Anchor Attachment Protein 1), shared by the four affected members of a large pedigree with multiple types of VA using whole-exome sequencing. GPAA1 encodes a glycosylphosphatidylinositol (GPI) transamidase complex protein. This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum (ER). We showed such variant led to scarce expression of GPAA1 protein in vascular endothelium and induced a localization change from ER membrane to cytoplasm and nucleus. In addition, expressing wild-type GPAA1 in endothelial cells had an effect to inhibit cell proliferation and migration, while expressing variant GPAA1 led to overgrowth and overmigration, indicating a loss of the quiescent status. Finally, a gpaa1-deficient zebrafish model displayed several types of developmental defects as well as vascular dysplasia, demonstrating that GPAA1 is involved in angiogenesis and vascular remodeling. Altogether, our results indicate that the rare coding variant in GPAA1 (c.968A > G) is causally related to familial forms of VAs.

血管异常（VAs）通常由多种酪氨酸激酶（TK）受体信号传导途径的变异（包括TIE2，PIK3CA和GNAQ / 11）引起，包括多种类型的肿瘤和畸形。然而，一部分具有VA临床特征的个体在这些基因中没有变异，这表明这些患者潜在的致病因素尚未发现，并且可能具有重叠的表型。在这里，我们在GPAA1（糖基磷脂酰肌醇固定锚附着蛋白1）的第七个外显子中发现了一个罕见的非同义变体（c.968A> G），该大同系的四个受影响成员与使用全外显子的多种类型的VA共享排序。GPAA1编码糖基磷脂酰肌醇（GPI）转酰胺酶复合蛋白。该复合物可协调GPI锚点与内质网（ER）中前体蛋白C末端的连接。我们显示这种变异导致血管内皮中GPAA1蛋白的稀缺表达，并引起从ER膜到细胞质和细胞核的定位变化。另外，在内皮细胞中表达野生型GPAA1具有抑制细胞增殖和迁移的作用，而表达变体GPAA1导致过度生长和过度迁移，表明失去了静止状态。最后，一个gpaa1缺陷的斑马鱼模型显示出几种类型的发育缺陷以及血管发育异常，表明GPAA1参与血管生成和血管重塑。总之，我们的结果表明GPAA1中的罕见编码变体（c.968A> G）与VA的家族形式有因果关系。