Skip to main content
PMC home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 1999 Jul;36(7):518–523.

Analysis of germline CDKN1C (p57KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation

W Lam 1, I Hatada 1, S Ohishi 1, T Mukai 1, J Joyce 1, T Cole 1, D Donnai 1, W Reik 1, P Schofield 1, E Maher 1
PMCID: PMC1734395  PMID: 10424811

Abstract

Beckwith-Wiedemann syndrome (BWS) is a human imprinting disorder with a variable phenotype. The major features are anterior abdominal wall defects including exomphalos (omphalocele), pre- and postnatal overgrowth, and macroglossia. Additional less frequent complications include specific developmental defects and a predisposition to embryonal tumours. BWS is genetically heterogeneous and epigenetic changes in the IGF2/H19 genes resulting in overexpression of IGF2 have been implicated in many cases. Recently germline mutations in the cyclin dependent kinase inhibitor gene CDKN1C (p57KIP2) have been reported in a variable minority of BWS patients. We have investigated a large series of familial and sporadic BWS patients for evidence of CDKN1C mutations by direct gene sequencing. A total of 70 patients with classical BWS were investigated; 54 were sporadic with no evidence of UPD and 16 were familial from seven kindreds. Novel germline CDKN1C mutations were identified in five probands, 3/7 (43%) familial cases and 2/54 (4%) sporadic cases. There was no association between germline CDKN1C mutations and IGF2 or H19 epigenotype abnormalities. The clinical phenotype of 13 BWS patients with germline CDKN1C mutations was compared to that of BWS patients with other defined types of molecular pathology. This showed a significantly higher frequency of exomphalos in the CDKN1C mutation cases (11/13) than in patients with an imprinting centre defect (associated with biallelic IGF2 expression and H19 silencing) (0/5, p<0.005) or patients with uniparental disomy (0/9, p<0.005). However, there was no association between germline CDKN1C mutations and risk of embryonal tumours. No CDKN1C mutations were identified in six non-BWS patients with overgrowth and Wilms tumour. These findings (1) show that germline CDKN1C mutations are a frequent cause of familial but not sporadic BWS, (2) suggest that CDKN1C mutations probably cause BWS independently of changes in IGF2/H19 imprinting, (3) provide evidence that aspects of the BWS phenotype may be correlated with the involvement of specific imprinted genes, and (4) link genotype-phenotype relationships in BWS and the results of murine experimental models of BWS.


Keywords: Beckwith-Wiedemann syndrome; CDKN1C (p57KIP2) mutation

Full Text

The Full Text of this article is available as a PDF (109.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barlow D. P. Gametic imprinting in mammals. Science. 1995 Dec 8;270(5242):1610–1613. doi: 10.1126/science.270.5242.1610. [DOI] [PubMed] [Google Scholar]
  2. Barton S. C., Surani M. A., Norris M. L. Role of paternal and maternal genomes in mouse development. 1984 Sep 27-Oct 3Nature. 311(5984):374–376. doi: 10.1038/311374a0. [DOI] [PubMed] [Google Scholar]
  3. Brown K. W., Gardner A., Williams J. C., Mott M. G., McDermott A., Maitland N. J. Paternal origin of 11p15 duplications in the Beckwith-Wiedemann syndrome. A new case and review of the literature. Cancer Genet Cytogenet. 1992 Jan;58(1):66–70. doi: 10.1016/0165-4608(92)90136-v. [DOI] [PubMed] [Google Scholar]
  4. Brown K. W., Villar A. J., Bickmore W., Clayton-Smith J., Catchpoole D., Maher E. R., Reik W. Imprinting mutation in the Beckwith-Wiedemann syndrome leads to biallelic IGF2 expression through an H19-independent pathway. Hum Mol Genet. 1996 Dec;5(12):2027–2032. doi: 10.1093/hmg/5.12.2027. [DOI] [PubMed] [Google Scholar]
  5. Catchpoole D., Lam W. W., Valler D., Temple I. K., Joyce J. A., Reik W., Schofield P. N., Maher E. R. Epigenetic modification and uniparental inheritance of H19 in Beckwith-Wiedemann syndrome. J Med Genet. 1997 May;34(5):353–359. doi: 10.1136/jmg.34.5.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Elliott M., Maher E. R. Beckwith-Wiedemann syndrome. J Med Genet. 1994 Jul;31(7):560–564. doi: 10.1136/jmg.31.7.560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hatada I., Inazawa J., Abe T., Nakayama M., Kaneko Y., Jinno Y., Niikawa N., Ohashi H., Fukushima Y., Iida K. Genomic imprinting of human p57KIP2 and its reduced expression in Wilms' tumors. Hum Mol Genet. 1996 Jun;5(6):783–788. doi: 10.1093/hmg/5.6.783. [DOI] [PubMed] [Google Scholar]
  8. Hatada I., Mukai T. Genomic imprinting of p57KIP2, a cyclin-dependent kinase inhibitor, in mouse. Nat Genet. 1995 Oct;11(2):204–206. doi: 10.1038/ng1095-204. [DOI] [PubMed] [Google Scholar]
  9. Hatada I., Nabetani A., Morisaki H., Xin Z., Ohishi S., Tonoki H., Niikawa N., Inoue M., Komoto Y., Okada A. New p57KIP2 mutations in Beckwith-Wiedemann syndrome. Hum Genet. 1997 Oct;100(5-6):681–683. doi: 10.1007/s004390050573. [DOI] [PubMed] [Google Scholar]
  10. Hatada I., Ohashi H., Fukushima Y., Kaneko Y., Inoue M., Komoto Y., Okada A., Ohishi S., Nabetani A., Morisaki H. An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome. Nat Genet. 1996 Oct;14(2):171–173. doi: 10.1038/ng1096-171. [DOI] [PubMed] [Google Scholar]
  11. Henry I., Bonaiti-Pellié C., Chehensse V., Beldjord C., Schwartz C., Utermann G., Junien C. Uniparental paternal disomy in a genetic cancer-predisposing syndrome. Nature. 1991 Jun 20;351(6328):665–667. doi: 10.1038/351665a0. [DOI] [PubMed] [Google Scholar]
  12. Joyce J. A., Lam W. K., Catchpoole D. J., Jenks P., Reik W., Maher E. R., Schofield P. N. Imprinting of IGF2 and H19: lack of reciprocity in sporadic Beckwith-Wiedemann syndrome. Hum Mol Genet. 1997 Sep;6(9):1543–1548. doi: 10.1093/hmg/6.9.1543. [DOI] [PubMed] [Google Scholar]
  13. Kondo M., Matsuoka S., Uchida K., Osada H., Nagatake M., Takagi K., Harper J. W., Takahashi T., Elledge S. J., Takahashi T. Selective maternal-allele loss in human lung cancers of the maternally expressed p57KIP2 gene at 11p15.5. Oncogene. 1996 Mar 21;12(6):1365–1368. [PubMed] [Google Scholar]
  14. Koufos A., Grundy P., Morgan K., Aleck K. A., Hadro T., Lampkin B. C., Kalbakji A., Cavenee W. K. Familial Wiedemann-Beckwith syndrome and a second Wilms tumor locus both map to 11p15.5. Am J Hum Genet. 1989 May;44(5):711–719. [PMC free article] [PubMed] [Google Scholar]
  15. Lee M. H., Reynisdóttir I., Massagué J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev. 1995 Mar 15;9(6):639–649. doi: 10.1101/gad.9.6.639. [DOI] [PubMed] [Google Scholar]
  16. Lee M. P., DeBaun M., Randhawa G., Reichard B. A., Elledge S. J., Feinberg A. P. Low frequency of p57KIP2 mutation in Beckwith-Wiedemann syndrome. Am J Hum Genet. 1997 Aug;61(2):304–309. doi: 10.1086/514858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lee M. P., Hu R. J., Johnson L. A., Feinberg A. P. Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements. Nat Genet. 1997 Feb;15(2):181–185. doi: 10.1038/ng0297-181. [DOI] [PubMed] [Google Scholar]
  18. Leighton P. A., Ingram R. S., Eggenschwiler J., Efstratiadis A., Tilghman S. M. Disruption of imprinting caused by deletion of the H19 gene region in mice. Nature. 1995 May 4;375(6526):34–39. doi: 10.1038/375034a0. [DOI] [PubMed] [Google Scholar]
  19. Matsuoka S., Edwards M. C., Bai C., Parker S., Zhang P., Baldini A., Harper J. W., Elledge S. J. p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev. 1995 Mar 15;9(6):650–662. doi: 10.1101/gad.9.6.650. [DOI] [PubMed] [Google Scholar]
  20. Matsuoka S., Thompson J. S., Edwards M. C., Bartletta J. M., Grundy P., Kalikin L. M., Harper J. W., Elledge S. J., Feinberg A. P. Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor, p57KIP2, on chromosome 11p15. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):3026–3030. doi: 10.1073/pnas.93.7.3026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. O'Keefe D., Dao D., Zhao L., Sanderson R., Warburton D., Weiss L., Anyane-Yeboa K., Tycko B. Coding mutations in p57KIP2 are present in some cases of Beckwith-Wiedemann syndrome but are rare or absent in Wilms tumors. Am J Hum Genet. 1997 Aug;61(2):295–303. doi: 10.1086/514854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ogawa O., Eccles M. R., Szeto J., McNoe L. A., Yun K., Maw M. A., Smith P. J., Reeve A. E. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour. Nature. 1993 Apr 22;362(6422):749–751. doi: 10.1038/362749a0. [DOI] [PubMed] [Google Scholar]
  23. Okamoto K., Morison I. M., Reeve A. E., Tommerup N., Wiedemann H. R., Friedrich U. Is p57KIP2 mutation a common mechanism for Beckwith-Wiedemann syndrome or somatic overgrowth? J Med Genet. 1998 Jan;35(1):86–86. doi: 10.1136/jmg.35.1.86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Orlow I., Iavarone A., Crider-Miller S. J., Bonilla F., Latres E., Lee M. H., Gerald W. L., Massagué J., Weissman B. E., Cordón-Cardó C. Cyclin-dependent kinase inhibitor p57KIP2 in soft tissue sarcomas and Wilms'tumors. Cancer Res. 1996 Mar 15;56(6):1219–1221. [PubMed] [Google Scholar]
  25. Paulsen M., Davies K. R., Bowden L. M., Villar A. J., Franck O., Fuermann M., Dean W. L., Moore T. F., Rodrigues N., Davies K. E. Syntenic organization of the mouse distal chromosome 7 imprinting cluster and the Beckwith-Wiedemann syndrome region in chromosome 11p15.5. Hum Mol Genet. 1998 Jul;7(7):1149–1159. doi: 10.1093/hmg/7.7.1149. [DOI] [PubMed] [Google Scholar]
  26. Ping A. J., Reeve A. E., Law D. J., Young M. R., Boehnke M., Feinberg A. P. Genetic linkage of Beckwith-Wiedemann syndrome to 11p15. Am J Hum Genet. 1989 May;44(5):720–723. [PMC free article] [PubMed] [Google Scholar]
  27. Reik W., Brown K. W., Schneid H., Le Bouc Y., Bickmore W., Maher E. R. Imprinting mutations in the Beckwith-Wiedemann syndrome suggested by altered imprinting pattern in the IGF2-H19 domain. Hum Mol Genet. 1995 Dec;4(12):2379–2385. doi: 10.1093/hmg/4.12.2379. [DOI] [PubMed] [Google Scholar]
  28. Reik W., Maher E. R. Imprinting in clusters: lessons from Beckwith-Wiedemann syndrome. Trends Genet. 1997 Aug;13(8):330–334. doi: 10.1016/s0168-9525(97)01200-6. [DOI] [PubMed] [Google Scholar]
  29. Shapiro M. B., Senapathy P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 1987 Sep 11;15(17):7155–7174. doi: 10.1093/nar/15.17.7155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Slatter R. E., Elliott M., Welham K., Carrera M., Schofield P. N., Barton D. E., Maher E. R. Mosaic uniparental disomy in Beckwith-Wiedemann syndrome. J Med Genet. 1994 Oct;31(10):749–753. doi: 10.1136/jmg.31.10.749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Slavotinek A., Gaunt L., Donnai D. Paternally inherited duplications of 11p15.5 and Beckwith-Wiedemann syndrome. J Med Genet. 1997 Oct;34(10):819–826. doi: 10.1136/jmg.34.10.819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Steenman M. J., Rainier S., Dobry C. J., Grundy P., Horon I. L., Feinberg A. P. Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms' tumour. Nat Genet. 1994 Jul;7(3):433–439. doi: 10.1038/ng0794-433. [DOI] [PubMed] [Google Scholar]
  33. Sun F. L., Dean W. L., Kelsey G., Allen N. D., Reik W. Transactivation of Igf2 in a mouse model of Beckwith-Wiedemann syndrome. Nature. 1997 Oct 23;389(6653):809–815. doi: 10.1038/39797. [DOI] [PubMed] [Google Scholar]
  34. Weksberg R., Shen D. R., Fei Y. L., Song Q. L., Squire J. Disruption of insulin-like growth factor 2 imprinting in Beckwith-Wiedemann syndrome. Nat Genet. 1993 Oct;5(2):143–150. doi: 10.1038/ng1093-143. [DOI] [PubMed] [Google Scholar]
  35. Weksberg R., Teshima I., Williams B. R., Greenberg C. R., Pueschel S. M., Chernos J. E., Fowlow S. B., Hoyme E., Anderson I. J., Whiteman D. A. Molecular characterization of cytogenetic alterations associated with the Beckwith-Wiedemann syndrome (BWS) phenotype refines the localization and suggests the gene for BWS is imprinted. Hum Mol Genet. 1993 May;2(5):549–556. doi: 10.1093/hmg/2.5.549. [DOI] [PubMed] [Google Scholar]
  36. Zhang P., Liégeois N. J., Wong C., Finegold M., Hou H., Thompson J. C., Silverman A., Harper J. W., DePinho R. A., Elledge S. J. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature. 1997 May 8;387(6629):151–158. doi: 10.1038/387151a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES