Forcet C, Etienne-Manneville S, Gaude H, Fournier L, Debilly S, Salmi M 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 14: 1283-1292

Laboratoire Génétique Moléculaire, Signalisation et Cancer, CNRS UMR 5201, Domaine Rockfeller, Lyon, France.
Human Molecular Genetics (Impact Factor: 6.39). 06/2005; 14(10):1283-92. DOI: 10.1093/hmg/ddi139
Source: PubMed


Germline mutations of the LKB1 gene are responsible for the cancer-prone Peutz-Jeghers syndrome (PJS). LKB1 encodes a serine-threonine kinase that acts as a regulator of cell cycle, metabolism and cell polarity. The majority of PJS missense mutations abolish LKB1 enzymatic activity and thereby impair all functions assigned to LKB1. Here, we have investigated the functional consequences of recurrent missense mutations identified in PJS and in sporadic tumors which map in the LKB1 C-terminal non-catalytic region. We report that these C-terminal mutations neither disrupt LKB1 kinase activity nor interfere with LKB1-induced growth arrest. However, these naturally occuring mutations lessened LKB1-mediated activation of the AMP-activated protein kinase (AMPK) and impaired downstream signaling. Furthermore, C-terminal mutations compromise LKB1 ability to establish and maintain polarity of both intestinal epithelial cells and migrating astrocytes. Consistent with these findings, mutational analysis reveals that the LKB1 tail exerts an essential function in the control of cell polarity. Overall, our results ascribe a crucial regulatory role to the LKB1 C-terminal region. Our findings further indicate that LKB1 tumor suppressor activity is likely to depend on the regulation of AMPK signaling and cell polarization.

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    • "development of malignancies (Forcet et al. 2005). Notably , the same subject carried two additional variants linked to thyroid carcinoma (RET Y791F, rs77724903) and Cowden-like syndrome (SDHB S163P, rs33927012), but was free of any type of neoplasia at age 97. "
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    ABSTRACT: To identify previously reported disease mutations that are compatible with extraordinary longevity, we screened the coding regions of the genomes of 44 Ashkenazi Jewish centenarians. Individual genome sequences were generated with 30× coverage on the Illumina HiSeq 2000 and single-nucleotide variants were called with the genome analysis toolkit (GATK). We identified 130 coding variants that were annotated as “pathogenic” or “likely pathogenic” based on the ClinVar database and that are infrequent in the general population. These variants were previously reported to cause a wide range of degenerative, neoplastic, and cardiac diseases with autosomal dominant, autosomal recessive, and X-linked inheritance. Several of these variants are located in genes that harbor actionable incidental findings, according to the recommendations of the American College of Medical Genetics. In addition, we found risk variants for late-onset neurodegenerative diseases, such as the APOE ε4 allele that was even present in a homozygous state in one centenarian who did not develop Alzheimer's disease. Our data demonstrate that the incidental finding of certain reported disease variants in an individual genome may not preclude an extraordinarily long life. When the observed variants are encountered in the context of clinical sequencing, it is thus important to exercise caution in justifying clinical decisions.
    09/2014; 2(5). DOI:10.1002/mgg3.86
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    • "Accordingly, the interaction domain for one of these proteins may be localized to codon 302, and therefore could explain the high cancer risk of mutations within this site. Moreover, the C-terminal domain of STK11 is important for binding STRAD, which is a protein that is possibly involved in MAPK signaling, control of the AMPK pathway (a key regulator of cellular metabolism), and control of cell polarity [14,15]. Taken together, these data suggest that the novel STK11 mutation, c.904C > T (p.Q302X), which was found in two unrelated Chinese PJS families, causes partial loss of the kinase domain and complete loss of the C-terminal domain, and may contribute to polyp formation and tumorgenesis through various mechanisms, such as loss of growth arrest, apoptosis, and loss of cell polarity. "
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    ABSTRACT: Peutz-Jeghers syndrome (PJS) is caused by mutations in the tumor suppressor gene, STK11, and is characterized by gastrointestinal hamartomas, melanin spots on the lips, and an increased risk of developing cancer. Blood samples were collected from two unrelated Chinese PJS families totaling 20 individuals (9 male and 11 females), including 6 PJS patients. The entire coding region of the STK11 gene was amplified by polymerase chain reaction and analyzed by direct sequencing. A novel mutation, c.904C > T, in exon 7 was identified in both families. A C > T substitution changed codon 302 from CAG (glutamine) to TAG (stop), truncating the STK11 protein, thus leading to the partial loss of the kinase domain and complete loss of the α-helix C-terminus. Furthermore, one PJS patient from each family was diagnosed with a visceral cancer, a colon cancer and a liver cancer respectively. We predict that this novel mutation, p.Q302X, is most likely responsible for development of the PJS phenotype and may even contribute to malignancy.
    BMC Medical Genetics 12/2011; 12(1):161. DOI:10.1186/1471-2350-12-161 · 2.08 Impact Factor
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    • "In 1998, point mutations in the STK11(LKB1) gene were described as inducing PJS (Hemminki et al., 1998; Jenne et al., 1998). STK11, mapped at 19p13.3, encodes a serine-threonine protein kinase that acts as a regulator of cell-cycle metabolism and cell polarity, with evidence of tumor suppressor functions (Forcet et al., 2005). Germline point mutations in STK11 have been identified in most patients with PJS, with partial or whole gene deletion in approximately 30% of these (Aretz et al., 2005; Resta et al., 2010). "
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    ABSTRACT: The Peutz-Jeghers syndrome (PJS) is an autosomal-dominant hamartomatous polyposis syndrome characterized by mucocutaneous pigmentation, gastrointestinal polyps and the increased risk of multiple cancers. The causative point mutation in the STK11 gene of most patients accounts for about 30% of the cases of partial and complete gene deletion. This is a report on a girl with PJS features, learning difficulties, dysmorphic features and cardiac malformation, bearing a de novo 1.1 Mb deletion at 19p13.3. This deletion encompasses at least 47 genes, including STK11. This is the first report on 19p13.3 deletion associated with a PJS phenotype, as well as other atypical manifestations, thereby implying a new contiguous gene syndrome.
    Genetics and Molecular Biology 10/2011; 34(4):557-61. DOI:10.1590/S1415-47572011005000044 · 1.20 Impact Factor
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