Novel and Recurrent Mutations of STK11 Gene in Six Chinese Cases with Peutz–Jeghers Syndrome

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• 作者：Limeng Dai (1)
  Liyuan Fu (1)
  Dan Liu (1)
  Kun Zhang (1)
  Yuanyuan Wu (1)
  Hui Meng (1)
  Bo Zhang (1)
  Xingying Guan (1)
  Hong Guo (1)
  Yun Bai (1)
  
• 关键词：STK11 ; Peutz–Jeghers syndrome ; P53 ; Mutation
• 刊名：Digestive Diseases and Sciences
• 出版年：2014
• 出版时间：August 2014
• 年：2014
• 卷：59
• 期：8
• 页码：1856-1861
• 全文大小：1,113 KB
• 参考文献：1. Beggs AD, Latchford AR, Vasen HF, et al. Peutz–Jeghers syndrome: a systematic review and recommendations for management. / Gut. 2010;59:975-86. CrossRef
  2. Buchet-Poyau K, Mehenni H, Radhakrishna U, Antonarakis SE. Search for the second Peutz–Jeghers syndrome locus: exclusion of the STK13, PRKCG, KLK10, and PSCD2 genes on chromosome 19 and the STK11IP gene on chromosome 2. / Cytogenet Genome Res. 2002;97:171-78. CrossRef
  3. Volikos E, Robinson J, Aittomaki K, et al. LKB1 exonic and whole gene deletions are a common cause of Peutz–Jeghers syndrome. / J Med Genet. 2006;43:e18. CrossRef
  4. Wang HH, Xie NN, Li QY, Hu YQ, Ren JL, Guleng B. Exome sequencing revealed novel germline mutations in Chinese Peutz–Jeghers syndrome patients. / Dig Dis Sci. (Epub ahead of print). doi:10.1007/s10620-013-2875-7 .
  5. Aretz S, Stienen D, Uhlhaas S, et al. High proportion of large genomic STK11 deletions in Peutz–Jeghers syndrome. / Hum Mutat. 2005;26:513-19. CrossRef
  6. Korsse SE, Peppelenbosch MP, van Veelen W. Targeting LKB1 signaling in cancer. / Biochim Biophys Acta. 2013;1835:194-10.
  7. Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers in the Peutz–Jeghers syndrome. / Clin Cancer Res. 2006;12:3209-215. CrossRef
  8. Boudeau J, Baas AF, Deak M, et al. MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm. / EMBO J. 2003;22:5102-114. CrossRef
  9. Forcet C, Etienne-Manneville S, Gaude H, et al. Functional analysis of Peutz–Jeghers mutations reveals that the LKB1 C-terminal region exerts a crucial role in regulating both the AMPK pathway and the cell polarity. / Hum Mol Genet. 2005;14:1283-292. CrossRef
  10. Wei C, Amos CI, Stephens LC, et al. Mutation of Lkb1 and p53 genes exert a cooperative effect on tumorigenesis. / Cancer Res. 2005;65:11297-1303. CrossRef
  11. Zeng PY, Berger SL. LKB1 is recruited to the p21/WAF1 promoter by p53 to mediate transcriptional activation. / Cancer Res. 2006;66:10701-0708. CrossRef
  12. Liu L, Du X, Nie J. A novel de novo mutation in LKB1 gene in a Chinese Peutz Jeghers syndrome patient significantly diminished p53 activity. / Clin Res Hepatol Gastroenterol. 2011;35:221-26. CrossRef
  13. Korsse SE, Biermann K, Offerhaus GJ, et al. Identification of molecular alterations in gastrointestinal carcinomas and dysplastic hamartomas in Peutz–Jeghers syndrome. / Carcinogenesis. 2013;34:1611-619. CrossRef
  
• 作者单位：Limeng Dai (1)
  Liyuan Fu (1)
  Dan Liu (1)
  Kun Zhang (1)
  Yuanyuan Wu (1)
  Hui Meng (1)
  Bo Zhang (1)
  Xingying Guan (1)
  Hong Guo (1)
  Yun Bai (1)
  
  1. Department of Medical Genetics, College of Basic Medical Science, Third Military Medical University, Chongqing, 400038, China
  
• ISSN：1573-2568

文摘

Background 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. Materials and Methods 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. Results 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. Conclusions 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.