A novel mutation in STK11 gene is associated with Peutz-Jeghers syndrome in Chinese patients

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: We predict that this novel mutation, p.Q302X, is most likely responsible for development of the PJS phenotype and may even contribute to malignancy.

Figure 1

Pedigree of the families with PJS. Roman numerals indicate generations and arabic numbers indicate individuals. Squares = males, circles = females. Affected individuals are denoted by solid symbols and unaffected individuals are denoted by open symbols. A slash denotes that the individual is deceased. The initial proband is indicated by an arrow, and participants in the DNA analysis are marked with an asterisk.

Figure 2

The germline nonsense mutation of the STK11 gene. Arrows indicate the position of the mutation and the underlines highlight the codon containing the mutation. The wide-type sequence CAG (glutamine) is altered to the mutant sequence TAG (stop) at codon 302, which leads to truncation of the STK11 protein.

Figure 3

Structural modeling of the wild-type and mutant proteins. The STK11 protein is mainly comprised of three major domains: the N-terminal non-catalytic domain in red, the catalytic kinase domain in green, and the C-terminal non-catalytic regulatory domain in blue. The mutation, p.Q302X, leads to partial loss of the kinase domain and complete loss of the C-terminal end of the α-helix.