A somatic mutation in PIK3CD unravels a novel candidate gene for lymphatic malformation
| Autor: | Wei Wang, Xin Ni, Yongli Guo, Nian Sun, Yanzhen Li, Zhiyong Liu, Jingang Gui, Yuanhu Liu, Lin Han, Jiangnan Du, Qiaoyin Liu, Jun Tai, Shengcai Wang, Xuexi Zhang, Jie Zhang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Candidate gene Class I Phosphatidylinositol 3-Kinases Somatic cell MTOR pathway Biology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Germline mutation PIK3CA Gene Mutation medicine Humans Pharmacology (medical) Child Lymphatic malformations Genetics (clinical) PI3K/AKT/mTOR pathway Lymphatic Vessels Mutation Lymphatic Abnormalities Research Endothelial Cells Correction PIK3CD General Medicine Novel mutations Lymphangiogenesis 030104 developmental biology Lymphatic system 030220 oncology & carcinogenesis Whole-exome sequencing Cancer research Medicine Signal Transduction |
| Zdroj: | Orphanet Journal of Rare Diseases, Vol 16, Iss 1, Pp 1-13 (2021) Orphanet Journal of Rare Diseases |
| ISSN: | 1750-1172 |
| Popis: | Background Lymphatic malformations (LMs) are benign congenital malformations that stem from the abnormal development of the lymphatic vessels during early embryogenesis. Somatic PIK3CA gene mutations are conventional cause leading to LMs. Both macrocystic and microcystic LMs arise due to lymphatic endothelial cell-autonomous defects, depending on the time in development at which PIK3CA gene mutation occurs. Recent study finds a PIK3CA mutation in 79% of LMs. However, discovering new genetic events in this disease is crucial to identify the molecular mechanism of the pathogenesis and further develop new targeted therapies. Results Here, we initially performed whole-exome sequencing in six children with LMs to find a new causal gene. Somatic mutations in PIK3CA (c.1633G > A [p. E545K] and PIK3CD (c.1997T > C [p.L666P]) were discovered in two different individuals. In vitro functional studies were conducted to demonstrate the pathogenicity of the novel mutation c.1997T > C in PIK3CD. We found that L666P promoted the cell proliferation and migration of human umbilical vein endothelial cells (HUVECs) and induced hyperactivation of the mTOR pathway. These findings indicate that the PIK3CD mutation affects downstream signalling in endothelial cells, which may impair normal lymphangiogenesis. Conclusions This study reveals a novel candidate gene associated with the development of LMs, which is consistent with previous researches. These findings in our study may offer a novel gene target for developing therapies, which acts in tight interaction with the previously known PIK3CA. |
| Databáze: | OpenAIRE |
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