De novo germline mutation in the serine–threonine kinase STK11/LKB1 gene associated with Peutz–Jeghers syndrome

Abstract

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease, characterized phenotypically by mucocutaneous pigmentation and hamartomatous polyposis. Affected patients are at an increased risk of developing gastrointestinal and other malignancies. Mutations in the STK11/LKB1 (LKB1) gene, which encodes for a serine-threonine kinase, have been identified as a genetic cause of PJS. Molecular analysis of the LKB1 gene in a simplex case of PJS revealed a substitution of cytosine (C) for guanine (G) at codon 246 in exon 6, resulting in the Tyr246X mutation. The nucleotide substitution leads to a premature stop codon at the 246 residue, predicting a truncated protein and presumed loss of kinase activity. Analysis of DNA from both parents of the PJS patient did not show this mutation, which is therefore a de novo mutation. We isolated DNA from microdissected gastrointestinal hamartomatous polyps in the PJS patient and investigated the loss of heterozygosity (LOH) at the LKB1 locus by real-time fluorescence polymerase chain reaction genotyping using a fluorescent resonance energy transfer technique. The results suggest a different mechanism from LOH in the formation of hamartomatous polyps.

Lkb1 is required for TGFβ-mediated myofibroblast differentiation

“…Interestingly, the observation of haploinsufficiency of Lkb1 in myofibroblast differentiation as measured by SMA reporter activity (Fig. 4D) resembles the situation in vivo in heterozygote PJS patients and mice, in which haploinsufficiency of Lkb1 leads to polyposis (Hernan et al, 2004;Jishage et al, 2002;Rossi et al, 2002). Thus, the role of Lkb1 in the differentiation of SM22-positive cells that was investigated here suggests that aberrant differentiation of the SM22-positive cell lineage in mice underlies polyposis.…”

“…A smaller, but still significant, decrease in (CAGA) 12 -luc activity was also noted in AdCre-infected Lkb1 lox/+ MEFs (16%; P=0.0014) (Fig. 1A, lox/+ bars), demonstrating haploinsufficiency of Lkb1 in this model and indicating similarity in this regard to the tumor-suppressor function of Lkb1 (Hernan et al, 2004;Jishage et al, 2002;Miyoshi et al, 2002;Rossi et al, 2002).…”

Oncogenic B-RAF Negatively Regulates the Tumor Suppressor LKB1 to Promote Melanoma Cell Proliferation

“…Secondly, our findings suggest that MEK and RAF inhibitors may be useful in the treatment of PJS by activating LKB1 when an intact LKB1 allele is present. Recent studies have shown that haploinsufficiency of LKB1 is sufficient for the formation of hamartomatous polyps in mouse models, and there is evidence that a wild-type allele of LKB1 can be found in the harmatomatous polyps from PJS patients (Hernan et al, 2004). Lastly, in addition to direct AMPK activators, strategies based on modulating post-translational modifications of LKB1, such as MEK and RAF inhibitors, that activate AMPK indirectly, could also be considered for the treatment of metabolic disorders.…”

LKB1 and AMPK Family Signaling: The Intimate Link Between Cell Polarity and Energy Metabolism

“…Recently, we proposed that PJS polyps are not premalignant and are a signpost to the malignant condition, not its direct obligate histological precursor (54). Polyps both in patients (30,47) as well as in murine models (9,57,85,92,127) retain the wild-type allele. Moreover, polyps removed from patients are polyclonal (30).…”