Clinics and Research in Hepatology and Gastroenterology
Original articleA novel de novo mutation in LKB1 gene in a Chinese Peutz Jeghers syndrome patient significantly diminished p53 activity☆
Introduction
Peutz Jeghers syndrome (PJS) is an autosomal dominant inherited disorder occurring in 1 of every 120,000 births [1]. It is characterized by the presence of hamartomatous polyps in the gastro-intestinal tract and by melanin spots on the lips, buccal mucosa, and digits [2]. In addition to these typical symptoms, patients often have an increased risk of gastro-intestinal malignancies and cancers at other sites, such as in breast, pancreas, ovary, uterus, lung and testicle [3], [4]. Genetic linkage studies have mapped the disease to genomic region 19p 13.3 and germ-line mutations in the LKB1 gene at this locus have been identified as a major reseason of PJS [5], [6], [7]. Human LKB1 (also known as STK11) gene encodes a 433-amino acid serine/threonine protein kinase [5], [6], consisting of 10 exons (nine coding exons), and codons 50-337 encode the catalytic kinase domain. Appromitely 70–80% of the PJS patients harbor germ-line mutations or deletions in the LKB1 gene. Studies of LKB1 mouse models show that Lkb1+/- mice develop gastro-intestinal polyposis and hepatocellular carcinomas, while Lkb1-/- embryos die during midgestation [8], [9].
The p53 gene is one of the most important and widely studied tumor suppressor genes. P53 controls the cell proliferation and apoptosis by regulating of the expression of various genes that are implicated in cell cycle arrest, DNA damage repair and apoptosis [10]. About 50% of human cancers have p53 gene mutations, suggesting that p53 inactivation is crucial for tumorgenesis [11]. It has been reported that LKB1 plays a critical role in p53-mediated cell apoptosis [12]. Gene knock-out studies have revealed that the Lkb1+/-/p53+/- mice showed a dramatically reduced life span and increased tumor incidence compared to the mice with either Lkb1 or p53 single gene knockout, indicating that p53 and Lkb1 gene mutations cooperate in tumor progression [13].
In this study, we identified a novel de novo mis-sense mutation in LKB1 gene from a Chinese PJS patient, and observed that the loss of LKB1 function in PJS patient resulted in diminished in p53 activity.
Section snippets
Patient
A 26-year-old woman was diagnosed clinically with PJS at the age of 18 years old. The patient had no relations to be affected. Diagnosis was based on histologically confirmed gastro-intestinal hamartomatous polyps after polypectomy and the presence of characteristic mucocutaneous pigmentation of the lips, buccal mucosa and fingers.
DNA and RNA extraction
Total genomic DNA was extracted from peripheral blood using the genomic DNA extraction Kit (Takara) according to the manufacturer's instructions. Total RNA was
A novel de novo mutation of LKB1 gene was identified in a Chinese PJS patient
In order to investigate the genetic characteristics of this Chinese PJS patient, the total genomic DNA was extracted from peripheral blood and the entire nine encoding exons of LKB1 gene were analyzed by PCR amplification. PCR samples were subjected to ligate into pGEM-T easy vectors and subcloned using the TA cloning system. A minimum of eight individual clonies were selected. Plasmid DNAs were isolated and used for DNA sequencing analysis. Sequencing analysis of the LKB1 gene revealed a
Discussion
LKB1 was initially characterized as a key determinant in Peutz-Jeghers syndrome, an inherited predisposition to gastro-intestinal and other cancers [2], [3], [4]. Till now, up to 200 kinds of mutations in LKB1 have been reported [15], [16], [17], [18]. However, the LKB1 mutation manners of Chinese PJS patients were limited. Here, we sequenced the entire nine encoding exons of LKB1 from a Chinese PJS sample. Unexpectedly, we observed a novel de novo mis-sense mutation of LKB1 in exon 1.
Previous
Conclusion
Our study presents the molecular characteristics of a Chinese PJS patient, increases the mutational spectrum of LKB1 gene, and provides a new insight useful for clinical diagnosis and genetic counseling of PJS families.
Conflicts of interest statement
No potential conflict of interest relevant to this article exists.
Acknowledgements
The authors thank all the patients and their families for participation in the study.
References (22)
Recognition of genetic syndromes in families with suspected hereditary colon cancer syndromes
Clin Gastroenterol Hepatol
(2004)- et al.
The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death
Mol Cell
(2001) - et al.
Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits: a syndrome of diagnostic significance
N Engl J Med
(1949) - et al.
Cancer and the Peutz-Jeghers syndrome
Gut
(1989) - et al.
Increased risk for cancer in patients with the Peutz-Jeghers syndrome
Ann Intern Med
(1998) - et al.
A serine/threonine kinase gene defective in Peutz-Jeghers syndrome
Nature
(1998) - et al.
Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase
Nat Genet
(1998) - et al.
Genetic heterogeneity in Peutz-Jeghers syndrome
Hum Mutat
(2000) - et al.
Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation
Nature
(2002) - et al.
Gastro-intestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice
Cancer Res
(2002)
Surfing the p53 network
Nature
Cited by (8)
Targeting LKB1 signaling in cancer
2013, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :In fact, LKB1 has been shown to interact with and phosphorylate PTEN, which was disrupted by introducing PJS-associated mutations in LKB1 [136,137]. In addition, LKB1 induces expression and nuclear export of PTEN resulting in reduced PI3K/AKT signaling and apoptosis [124,137,138]. This LKB1-mediated nuclear export of PTEN has been shown to be independent of AMPK/mTOR signaling [138].
A 23-Nucleotide Deletion in STK11 Gene Causes Peutz–Jeghers Syndrome and Malignancy in a Chinese Patient Without a Positive Family History
2017, Digestive Diseases and Sciences
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Supported by National Natural Science Foundation of China, NO. 60601018.