A novel variant in GPAA1 , encoding a GPI transamidase complex protein, causes inherited vascular anomalies with various
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ORIGINAL INVESTIGATION
A novel variant in GPAA1, encoding a GPI transamidase complex protein, causes inherited vascular anomalies with various phenotypes Yongyun Li1,2 · Liu Yang3 · Jie Yang1,2 · Jiahao Shi1,2 · Peiwei Chai1,2 · Shengfang Ge1,2 · Yefei Wang1,2 · Xianqun Fan1,2 · Renbing Jia1,2 Received: 4 April 2020 / Accepted: 1 June 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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 gpaa1deficient 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. Abbreviations VA Vascular anomaly IH Infantile hemangioma Yongyun Li and Liu Yang are co-first authors of this report. Yefei Wang, Xianqun Fan, and Renbing Jia are co-corresponding authors of this report. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00439-020-02192-w) contains supplementary material, which is available to authorized users. * Renbing Jia [email protected] 1
Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai 200001, China
2
Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
3
The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
CH Congenital hemangioma CM Capillary malformation VM Venous malformation CVM Cavernous venous malformation TK Tyrosine kinase V
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