Two missense STK11 gene variations impaired LKB1/adenosine monophosphate-activated protein kinase signaling in Peutz-Jeghers syndrome

ARTICLE HIGHLIGHTS

Research background

Peutz-Jeghers syndrome (PJS) is a rare hereditary tumor disease with autosomal dominant inheritance that primarily results from mutations in the STK11 gene. While certain missense variations of the STK11 gene have been identified and classified as pathogenic or likely pathogenic, numerous missense variations still remain as variants of uncertain significance (VUS). This ambiguity makes it challenging to establish the association between these variations and PJS, which poses significant challenges for clinical treatment management and fertility selection.

Research motivation

Among the 9 PJS families evaluated at our hospital, 2 patients with PJS were identified as having missense variations through whole-exome sequencing and were classified as VUS. Understanding how the function of STK11 is disrupted may contribute to a better understanding of the pathogenesis of PJS and the molecular mechanisms involved in the carcinogenesis process. Clarifying the pathogenicity of variations can offer patients the most appropriate reproductive guidance.

Research objectives

To clarify the pathogenicity of these two missense variations and to better provide patients with health management and fertility guidance.

Research methods

This study used whole-exome gene sequencing and Sanger sequencing methods to identify gene variants, combining bioinformatics analysis, quantitative polymerase chain reaction, immunoblotting, immunohistochemistry, and a variety of in vitro and in vivo functional assays to investigate pathogenicity.

Research results

Bioinformatics software analysis indicated that these two missense variants are deleterious. The phosphorylation levels of adenosine monophosphate-activated protein kinase (AMPK) and liver kinase B1 in the variant group were significantly lower than those in the wild-type group. Both missense STK11 variants promoted the proliferation of HeLa cells. The expression of phosphorylated-AMPK was significantly lower in PJS patients with a missense variant in gastric, colon, and uterine polyps compared to non-PJS patients. These missense variants inactivate the STK11 gene, disrupting the regulation of downstream AMPK proteins, thereby mediating the occurrence of PJS. As a result, they are interpreted as likely pathogenic, providing valuable information for patients in reproductive decision-making.

Research conclusions

These findings provide a basis for further research on and reanalysis of clinical decision making related to rare disease missense VUS.

Research perspectives

Further investigation into the role of STK11 gene in mediating PJS is required. Identifying the pathogenicity of more missense VUS is crucial to offer more accurate medical services for patients.