Loss of LKB1 Kinase Activity in Peutz-Jeghers Syndrome, and Evidence for Allelic and Locus Heterogeneity Hamid Mehenni, Corinne Gehrig, Jun-ichi Nezu,

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Loss of LKB1 Kinase Activity in Peutz-Jeghers Syndrome, and Evidence for Allelic and Locus Heterogeneity Hamid Mehenni, Corinne Gehrig, Jun-ichi Nezu, Asuka Oku, Miyuki Shimane, Colette Rossier, Nicolas Guex, Jean-Louis Blouin, Hamish S. Scott, Stylianos E. Antonarakis The American Journal of Human Genetics Volume 63, Issue 6, Pages 1641-1650 (December 1998) DOI: 10.1086/302159 Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 1 Nucleotide sequences of the LKB1 mutations identified in the present study. Sequences are in pairs, which include the normal sequence (left) and the mutant sequence (right). The identity of the PJS family in which each mutation was found is denoted above each mutant sequence. The sequences of the mutant alleles were obtained after cloning of the PCR products (see Families and Methods). The American Journal of Human Genetics 1998 63, 1641-1650DOI: (10.1086/302159) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 2 Schematic representation of the LKB1 gene (top) and protein (bottom). The exons are depicted as striped boxes; the intron sizes are not to scale. The different subdomains (I–IX) of the kinase domain of LKB1, as described by Hanks and Hunter 1995, are depicted (bottom). The mutations described in the present study are shown above the genomic structure. The amino acid substitutions or deletions are also shown in the schematic of the predicted protein. The amino acid lesions shown in italics have been described by Avizienyte et al. (1998) and Hemminki et al. (1998). The mutation in italics and underlined has been described in the Xenopus XEEK1 (Su et al. 1996). The American Journal of Human Genetics 1998 63, 1641-1650DOI: (10.1086/302159) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 3 Autophosphorylation assays of the wild-type and mutant LKB1 recombinant proteins, as described in Families and Methods. The lower panel shows the results of western blotting by use of the anti-myc antibody. The top panel reveals that the wild-type LKB1 is autophosphorylated, whereas the same amount of each of the mutants tested, including the K78I, D176N, W308C, and L67P, shows either no or dramatically reduced autophosphorylation. The American Journal of Human Genetics 1998 63, 1641-1650DOI: (10.1086/302159) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 4 Stereo images of the catalytic core of LKB1 in the presence of ATP after modeling (see Families and Methods). The normal LKB1 is shown in the middle, for easier comparison with the mutants; the D176N mutant is on the top, and the K78I is on the bottom. The protein backbone is shown in blue, whereas side chains and ATP are shown in the following colors: C, white; O, red; N, blue; P, orange; S, yellow; H, cyan. Two Mn++ atoms are shown as gray balls. Both mutations greatly disrupt the normal chemical contacts in the catalytic core (see the Protein Modeling subsection). The American Journal of Human Genetics 1998 63, 1641-1650DOI: (10.1086/302159) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 5 Overall fold of the LKB1 protein modeling. The β-strand that would be removed by the deletion of tetrapeptide LMGD is shown in red. ATP is added in the catalytic core. The D176 side chain that is mutated in family PJS05 is shown in green. The side chain of K78 is shown in purple. The W308 side chain mutated in PJS04 and in C158, which probably forms a disulfide bridge with the mutant W308C, is shown in black. L67, which is mutated to L67P (Hemminki et al. 1998), is shown in yellow. The American Journal of Human Genetics 1998 63, 1641-1650DOI: (10.1086/302159) Copyright © 1998 The American Society of Human Genetics Terms and Conditions