Pathogenic mutations in the serine/threonine kinase STK11 (alias LKB1) cause Peutz-Jeghers syndrome (PJS) in most affected individuals. However, in a considerable number of PJS-patients mutations cannot be detected in STK11 suggesting genetic heterogeneity. One PJS family without STK11 mutations (PJS07) has previously been described with significant evidence for linkage to a second potential PJS locus on 19q13.3-->q13.4. In this study we investigated candidate genes within markers D19S180 and D19S254, since multipoint linkage analysis yielded significant LOD scores for this region in this family. Four genes in the region (cytohesin 2: PSCD2, kallikrein 10: KLK10, protein kinase C gamma: PRKCG, and serine/threonine kinase 13: STK13) potentially involved in growth inhibitory pathways or in the pathophysiology of can- cer, were considered as candidates. We first determined the genomic structure of the PSCD2 and PRKCG genes, and performed mutation analysis of all exons and exon-intron junctions of the four genes, in the PJS07 family. No pathogenic mutation was identified in these four genes in affected individuals. A very rare polymorphism resulting in a conserved amino acid change Lys to Arg was found in PSCD2. These data provide considerable evidence for exclusion of these four genes as candidates for the second locus on 19q13.3-->q13.4 in PJS. Finally, we also excluded the recently identified STK11-interacting protein gene (STK11IP, alias LIP1) mapped in 2q36 as candidate for PJS in the PJS07 family, although this could be a good candidate in other non-STK11/LKB1 families.
Copyright 2002 S. Karger AG, Basel