Germline mutations in LKB1 (also known as STK11) on 19p13.3 were initially identified through positional cloning. LKB1 mutations have subsequently been identified in most, but not all, Peutz-Jeghers families, suggesting that additional loci may be involved.17 Families that do not harbor an LKB1 mutation do not differ by clinical manifestations or ethnicity from families with LKB1 mutations. Individuals with nonfamilial (de novo) Peutz-Jeghers often display the same germline LKB1 mutations as those found in individuals with a family history of this syndrome.17
LKB1 functions as a tumor suppressor gene whose protein physically associates with TP53 to regulate TP53-dependent apoptosis pathways.20,21 LKB1 also interacts with PTEN, which is responsible for other hereditary hamar-toma syndromes, and STRAD and MO25a, which regulate epithelial polarity.22,23 LKB1 encodes a 433 amino acid protein that is present in both the cytoplasm and the nucleus. The kinase domain resides within codons 50 to 337 of LKB1 and shares limited homology with other serine-threonine and tyrosine kinase family members. Most germline mutations in LKB1 result in protein truncation; however, rare missense mutations within the kinase domain have been observed.21
Inactivation of this tumor suppressor gene is a critical early event in the development of hamartomas and adenocarcinomas.24 Adenocarcinomas in patients with Peutz-Jeghers syndrome demonstrate altered TP53 expression and loss of heterozygosity (LOH) in 17p and 18q. Microsatellite instability, LOH near the APC gene, or KRAS mutations were identified in these tumors.24
Was this article helpful?
Finally! You Can Put All Your Worries To Rest! You Can Now Instantly Learn Some Little-Known But Highly Effective Tips For Successful Single Parenting! Understand Your Role As A Single Motherfather, And Learn How To Give Your Child The Love Of Both Parents Single Handedly.