STK11 – Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is an autosomal dominant hamartomatous polyposis disorder characterized by mucocutaneous pigmentation and gastrointestinal polyps with high cancer risk. Germline mutations in the serine/threonine kinase gene STK11 disrupt its tumor-suppressor function, leading to intestinal hamartomas and extraintestinal neoplasms. STK11 was first implicated in PJS in 1998, with a three-generation kindred harboring a frameshift in exon 1 and loss of kinase activity in polyps (PMID:9425897).

Clinical validity of the STK11–PJS association is Definitive based on mutations in >200 unrelated families, segregation in multi‐generation pedigrees, and concordant functional data. Germline STK11 defects have been identified in 33 PJS patients across six families, with complete co-segregation in affected relatives and no detection in controls (PMID:9887330). Loss of heterozygosity at 19p13.3 in 70% of PJS adenocarcinomas confirms a two-hit tumor suppressor mechanism (PMID:9850045).

Genetic evidence supports autosomal dominant inheritance with high penetrance. Segregation analysis documents at least 2 additional affected relatives beyond probands in kindreds. Over 100 distinct STK11 variants—truncating (frameshift, nonsense), missense, splice‐site, and large‐scale deletions—have been reported, with recurrent hotspots in exons 1, 6, 7 and 8. One representative frameshift is c.157dup (p.Asp53fs) observed in multiple families. No common founder variant is apparent; de novo events account for ~30% of cases.

Functional studies define loss of STK11 kinase activity and disrupted cytoplasmic retention as key pathogenic mechanisms. Mutant LKB1 proteins (e.g., K78I, D176N) exhibit abolished autophosphorylation and fail to form the LKB1–STRAD–MO25 complex, impairing AMPK activation and cell polarity (PMID:9837816; PMID:12805220). Conditional knockout in mouse pancreas recapitulates acinar polarity defects and cystadenomas, underscoring haploinsufficiency in vivo.

Although most PJS cases map to STK11, ~10% of clinically diagnosed individuals lack detectable mutations, suggesting locus heterogeneity or mosaicism. Silent and intronic variants (e.g., c.597G>A) can induce aberrant splicing, complicating genetic testing. No strong evidence refutes STK11’s role in classic PJS.

Together, multi-family segregation, comprehensive variant spectrum, and mechanistic models conclusively link STK11 to Peutz-Jeghers syndrome. STK11 testing enables predictive diagnosis, tailored surveillance, and family counseling. Key Take-home: Germline STK11 inactivation is the definitive cause of PJS, justifying early genetic screening and endoscopic surveillance in at-risk individuals.

References

• Nature genetics • 1998 • Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase STK11 PMID:9425897
• Human molecular genetics • 1999 • Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer PMID:9887330
• Cancer research • 1998 • Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome PMID:9850045
• American Journal of Human Genetics • 1998 • Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity PMID:9837816
• The EMBO Journal • 2003 • Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD PMID:12805220
• Oncogene • 2006 • A novel mutation of STK11/LKB1 gene leads to the loss of cell growth inhibition in head and neck squamous cell carcinoma PMID:16407837

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