Department of Medical Genetics, College of Basic Medical Science, Third Military Medical University, Chongqing, 400038, China.
Dig Dis Sci. 2014 Aug;59(8):1856-61. doi: 10.1007/s10620-014-3077-7. Epub 2014 Mar 7.
The serine/threonine kinase 11 (STK11) gene is the main causal gene in Peutz-Jeghers syndrome (PJS). Abnormal STK11 may increase cancer risk of PJS patients via affecting its target proteins such as P53, AMPK, and PTEN. In this study, we investigated the molecular basis of six Chinese PJS patients.
Blood samples were collected from four Chinese PJS families and two sporadic patients. The entire coding region of the STK11 gene was amplified by polymerase chain reaction and analyzed by direct sequencing. Functions of mutants were assessed by PolyPhen-2, Swiss-Model software, and luciferase reporter assay.
Novel mutations (c.842_843insC, c.804_805insG, and c.922T>G) and recurrent mutations (c.526G>A, c.180C>G, and c.1062C>G) were identified. Missense mutation c.922T>G and c.526G>A were predicted as probably damaging by PolyPhen-2, while c.1062C>G was benign. Mutation c.108C>G was a nonsense mutation. The 284Ter mutants of c.842_843insC and c.804_805insG significantly diminished the capacity of P53 activity in 293FT cells.
Our results support that STK11 gene mutations underlie Chinese patients with PJS. Mutation involving partial kinase domain disrupts normal function of STK11. Our results also enlarge the spectrum of STK11 variants in PJS patients.
丝氨酸/苏氨酸激酶 11（STK11）基因是 Peutz-Jeghers 综合征（PJS）的主要致病基因。异常的 STK11 可能通过影响其靶蛋白如 P53、AMPK 和 PTEN 来增加 PJS 患者的癌症风险。在这项研究中，我们研究了六位中国 PJS 患者的分子基础。
采集了四个中国 PJS 家系和两个散发性患者的血样。通过聚合酶链反应扩增 STK11 基因的整个编码区，并进行直接测序分析。通过 PolyPhen-2、Swiss-Model 软件和荧光素酶报告基因检测评估突变体的功能。
发现了新的突变（c.842_843insC、c.804_805insG 和 c.922T>G）和复发性突变（c.526G>A、c.180C>G 和 c.1062C>G）。错义突变 c.922T>G 和 c.526G>A 被 PolyPhen-2 预测为可能有害，而 c.1062C>G 为良性。c.108C>G 是无义突变。c.842_843insC 和 c.804_805insG 的 284Ter 突变显著降低了 293FT 细胞中 P53 活性。
我们的结果支持 STK11 基因突变是中国 PJS 患者的致病原因。涉及部分激酶结构域的突变破坏了 STK11 的正常功能。我们的结果还扩大了 PJS 患者中 STK11 变异的谱。
