Two missense STK11 gene variations impaired LKB1/adenosine monophosphate-activated protein kinase signaling in Peutz-Jeghers syndrome  

作　　者：Jin Liu Si-Cong Zeng An Wang Hai-Ying Cheng Qian-Jun Zhang Guang-Xiu Lu 

机构地区：[1]Hunan Guangxiu Hospital,Hunan Normal University,Changsha 410000,Hunan Province,China [2]Scientific Research Department,Reproductive and Genetic Hospital of Citic-Xiangya,Changsha 410000,Hunan Province,China

出　　处：《World Journal of Gastrointestinal Oncology》2024年第4期1532-1546,共15页世界胃肠肿瘤学杂志（英文版）（电子版）

基　　金：Supported by the Natural Science Foundation of Hunan Province,China,No.2023JJ30422.

摘　　要：BACKGROUND Peutz-Jeghers syndrome(PJS)is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11(STK11/LKB1)gene mutations.Preimplantation genetic testing can protect a patient’s offspring from mutated genes;however,some variations in this gene have been interpreted as variants of uncertain significance(VUS),which complicate reproductive decision-making in genetic counseling.AIM To identify the pathogenicity of two missense variants and provide clinical guidance.METHODS Whole exome gene sequencing and Sanger sequencing were performed on the peripheral blood of patients with PJS treated at the Reproductive and Genetic Hospital of Citic-Xiangya.Software was employed to predict the protein structure,conservation,and pathogenicity of the two missense variation sites in patients with PJS.Additionally,plasmids were constructed and transfected into HeLa cells to observe cell growth.The differences in signal pathway expression between the variant group and the wild-type group were compared using western blot and immunohistochemistry.Statistical analysis was performed using one-way analysis of variance.P<0.05 was considered statistically significant.RESULTS We identified two missense STK11 gene VUS[c.889A>G(p.Arg297Gly)and c.733C>T(p.Leu245Phe)]in 9 unrelated PJS families who were seeking reproductive assistance.The two missense VUS were located in the catalytic domain of serine/threonine kinase,which is a key structure of the liver kinase B1(LKB1)protein.In vitro experiments showed that the phosphorylation levels of adenosine monophosphate-activated protein kinase(AMPK)at Thr172 and LKB1 at Ser428 were significantly higher in transfected variation-type cells than in wild-type cells.In addition,the two missense STK11 variants promoted the proliferation of HeLa cells.Subsequent immunohistochemical analysis showed that phosphorylated-AMPK(Thr172)expression was significantly lower in gastric,colonic,and uterine polyps from PJS patients with missense variations than in non-PJS patients.Our fi

关 键 词：MISSENSE STK11 Peutz-Jeghers syndrome Rare disease Genetic counseling Assisted reproductive technique 

分 类 号：R735.7[医药卫生—肿瘤]