Chromosomal location and mode of inheritance

PJS is an autosomal dominant trait with nearly complete penetrance. The PJS gene, LKB1 (STK11), maps to 19p13.3, and there is some evidence suggestive of locus heterogeneity {1210}.

Gene structure

LKB1 consists of 9 coding exons. The open reading frame consists of 1302 base pairs, corresponding to 433 amino acids. Codons 50 to 337 encode the catalytic kinase domain of the gene.

Gene product

The human LKB1 gene is ubiquitously expressed in adults {853, 690}. It encodes a protein of 433 amino acids which possesses a serine/threonine kinase domain framed by a short N-ter-minus sequence (48 residues) and a more extended C-terminus region of 122 amino acids {853, 690}. LKB1 shares a significant sequence similarity with the Saccharomyces cerevisiae SNF1 kinase which phosphorylates transcriptional repressor and regulates glucose-repressible genes. Homologs of LKB1 have been identified in several species including mouse, Xenopus, and Caenorhabditis elegans {1852, 1768,

2072}. Sequence alignments revealed that these proteins are most conserved within the kinase domain, with 96% of identity between human and mouse and 42% identity between human and the nematode. Human LKB1 contains a nuclear localization signal (NLS) flanking the N-terminus part of the catalytic domain {1343, 1768} and a putative prenylation motif within the C-terminus {325}. The LKB1 gene product is located both in the nucleus and in the cytoplasm {1343}. LKB1 displays an autocatalytic activity in vitro, and is the substrate of the

Fig. 4.11 Structure of the LKB1 gene. Germline mutations in Peutz-Jeghers patients are most frequent in the kinase domain.

cAMP-dependent protein kinase (PKA) {325}. Although the function of LKB1 remains to be determined, it is worth noting that PAR-4, the C.elegans orthologue of LKB1, is required for establishing polarity during the first cell cycles of the embryo {2072}. PAR-4 expression is also essential for embryonic viability and for intestinal organogenesis. Since the cardinal clinical feature of PJS is the presence of intestinal hamartomatous polyps, it appears plausible that the function of LKB1 has been conserved across evolution as it exerts a key regulatory role during intestinal development.

Gene mutations and their relationship to clinical manifestations

Germline mutations are usually truncating, but missense type mutations have also been described {853, 690}. Wild type LKB1 is capable of autophosphory-lation {1210, 2176}, and the effect of missense mutations occurring in the kinase domain can be evaluated observing this property in autophosphorylation assays. Somatic mutations of LKB1 in tumours have been reported but are rare.

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