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Vol. 97, No. 3-4, 2002
Issue release date: 2002
Cytogenet Genome Res 97:171–178 (2002)
(DOI:10.1159/000066620)

Search for the second Peutz-Jeghers syndrome locus: exclusion of the STK13, PRKCG, KLK10, and PSCD2 genes on chromosome 19 and the STK11IP gene on chromosome 2

Buchet-Poyau K. · Mehenni H. · Radhakrishna U. · Antonarakis S.E.
Division of Medical Genetics, Geneva University Medical School, and University Hospitals, Geneva (Switzerland)

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Abstract

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.   



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References

  1. Al-Maghtheh M, Vithana EN, Inglehearn CF, Moore T, Bird AC, Bhattacharya SS: Segregation of a PRKCG mutation in two RP11 families. Am J hum Genet 62:1248–1252 (1998).
  2. Bernard M, Sanseau P, Henry C, Couturier A, Prigent C: Cloning of STK13, a third human protein kinase related to Drosophila aurora and budding yeast Ipl1 that maps on chromosome 19q13.3→qter. Genomics 53:406–409 (1998).
  3. Black JD: Protein kinase C-mediated regulation of the cell cycle. Front Biosci 5:D406–423 (2000).

    External Resources

  4. Chardin P, Paris S, Antonny B, Robineau S, Beraud-Dufour S, Jackson CL, Chabre M: A human exchange factor for ARF contains Sec7- and pleckstrin-homology domains. Nature 384:481–484 (1996).
  5. Cherfils J, Menetrey J, Mathieu M, Le Bras G, Robineau S, Beraud-Dufour S, Antonny B, Chardin P: Structure of the Sec7 domain of the Arf exchange factor ARNO. Nature 392:101–105 (1998).
  6. Clemens MJ, Trayner I, Menaya J: The role of protein kinase C isoenzymes in the regulation of cell proliferation and differentiation. J Cell Sci 103:881–887 (1992).
  7. Collins SP, Reoma JL, Gamm DM, Uhler MD: LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo. Biochem J 345:673–80 (2000).
  8. Frank S, Upender S, Hansen SH, Casanova JE: ARNO is a guanine nucleotide exchange factor for ADP-ribosylation factor 6. J biol Chem 273:23–27 (1998a).
  9. Frank SR, Hatfield JC, Casanova JE: Remodeling of the actin cytoskeleton is coordinately regulated by protein kinase C and the ADP-ribosylation factor nucleotide exchange factor ARNO. Mol Biol Cell 9:3133–3146 (1998b).
  10. Giet R, Prigent C: Aurora/Ipl1p-related kinases, a new oncogenic family of mitotic serine-threonine kinases. J Cell Sci 112:3591–3601 (1999).
  11. Goyal J, Smith KM, Cowan JM, Wazer DE, Lee SW, Band V: The role for NES1 serine protease as a novel tumor suppressor. Cancer Res 58:4782–4786 (1998).
  12. Harvey TJ, Hooper JD, Myers SA, Stephenson SA, Ashworth LK, Clements JA: Tissue-specific expression patterns and fine mapping of the human kallikrein (KLK) locus on proximal 19q13.4. J biol Chem 275:37397–37406 (2000).
  13. Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Hoglund P, Jarvinen H, Kristo P, Pelin K, Ridanpaa M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A, Aaltonen LA: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391:184–187 (1998).
  14. Hemminki A, Tomlinson I, Markie D, Jarvinen H, Sistonen P, Bjorkqvist AM, Knuutila S, Salovaara R, Bodmer W, Shibata D, de la Chapelle A, Aaltonen LA: Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nature Genet 15:87–90 (1997).
  15. International Human Genome Sequencing Consortium: Initial sequencing and analysis of the human genome. Nature 409:860–921 (2001).
  16. Jackson TR, Kearns BG, Theibert AB: Cytohesins and centaurins: mediators of PI 3-kinase-regulated Arf signaling. Trends Biochem Sci 25:489–495 (2000).

    External Resources

  17. Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Muller O, Back W, Zimmer M: Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nature Genet 18:38–43 (1998).
  18. Jiang CY, Esufali S, Berk T, Gallinger S, Cohen Z, Tobi M, Redston M, Bapat B: STK11/LKB1 germline mutations are not identified in most Peutz-Jeghers syndrome patients. Clin Genet 56:136–141 (1999).
  19. Kimura M, Matsuda Y, Yoshioka T, Okano Y: Cell cycle-dependent expression and centrosome localization of a third human aurora/Ipl1-related protein kinase, AIK3. J biol Chem 274:7334–7340 (1999).
  20. Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C, Parsons R: Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genet 16:64–67 (1997).
  21. Luo L, Herbrick JA, Scherer SW, Beatty B, Squire J, Diamandis EP: Structural characterization and mapping of the normal epithelial cell-specific 1 gene. Biochem biophys Res Commun 247:580–586 (1998).

    External Resources

  22. Marneros AG, Mehenni H, Krieg T, Antonarakis SE, Olsen BR: Gene for the human transmembrane-type protein tyrosine phosphatase H (PTPRH): genomic structure, fine-mapping and its exclusion as a candidate for Peutz-Jeghers syndrome. Cytogenet Cell Genet 92:213–216 (2001).
  23. Mehenni H, Blouin JL, Radhakrishna U, Bhardwaj SS, Bhardwaj K, Dixit VB, Richards KF, Bermejo-Fenoll A, Leal AS, Raval RC, Antonarakis SE: Peutz-Jeghers syndrome: confirmation of linkage to chromosome 19p13.3 and identification of a potential second locus, on 19q13.4. Am J hum Genet 61:1327–1334 (1997).
  24. Mehenni H, Gehrig C, Nezu J, Oku A, Shimane M, Rossier C, Guex N, Blouin JL, Scott HS, Antonarakis SE: Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am J hum Genet 63:1641–1650 (1998).
  25. Olschwang S, Markie D, Seal S, Neale K, Phillips R, Cottrell S, Ellis I, Hodgson S, Zauber P, Spigelman A, Iwama T, Loff S, McKeown C, Marchese C, Sampson J, Davies S, Talbot I, Wyke J, Thomas G, Bodmer W, Hemminki A, Avizienyte E, de la Chapelle A, Aaltonen L, Tomlinson I, et al: Peutz-Jeghers disease: most, but not all, families are compatible with linkage to 19p13.3. J med Genet 35:42–44 (1998).
  26. Ron D, Kazanietz MG: New insights into the regulation of protein kinase C and novel phorbol ester receptors. FASEB J 13:1658–1676 (1999).
  27. Rowan A, Churchman M, Jefferey R, Hanby A, Poulsom R, Tomlinson I: In situ analysis of LKB1/STK11 mRNA expression in human normal tissues and tumours. J Pathol 192:203–206 (2000).
  28. Santy LC, Frank SR, Hatfield JC, Casanova JE: Regulation of ARNO nucleotide exchange by a PH domain electrostatic switch. Curr Biol 9:1173–1176 (1999).
  29. Smith DP, Rayter SI, Niederlander C, Spicer J, Jones CM, Ashworth A: LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1. Hum molec Genet 10:2869–2877 (2001).

    External Resources

  30. Spigelman AD, Murday V, Phillips RK: Cancer and the Peutz-Jeghers syndrome. Gut 30:1588–1590 (1989).
  31. Thompson JD, Higgins DG, Gibson TJ: CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucl Acids Res 22:4673–4680 (1994).
  32. Tiainen M, Ylikorkala A, Makela TP: Growth suppression by Lkb1 is mediated by a G(1) cell cycle arrest. Proc natl Acad Sci, USA 96:9248–9251 (1999).
  33. Vazquez F, Sellers WR: The PTEN tumor suppressor protein: an antagonist of phosphoinositide 3-kinase signaling. Biochim biophys Acta 1470:M21–35 (2000).
  34. Westerman AM, Entius MM, Boor PPC, Koole R, de Baar E, Offerhaus GJA, Lubinski J, Lindhout D, Halley DJJ, de Rooij FWM, Wilson JHP: Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families. Hum Mutat 13:476–481 (1999).


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