Epigenetic modification and uniparental inheritance of H19 in Beckwith-Wiedemann syndrome.

D Catchpoole, W W Lam, D Valler, I K Temple, J A Joyce, W Reik, P N Schofield, E R Maher

Cambridge University Department of Pathology, UK.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome associated with a characteristic pattern of visceromegaly and predisposition to childhood tumours. BWS is a genetically heterogeneous disorder; most cases are sporadic but approximately 15% are familial and a small number of BWS patients have cytogenetic abnormalities involving chromosome 11p15. Genomic imprinting effects have been implicated in familial and non-familial BWS. We have investigated the molecular pathology of 106 sporadic BWS cases; 17% (14/83) of informative cases had uniparental disomy (UPD) for chromosome 11p15.5. In each case UPD appeared to result from a postzygotic event resulting in mosaicism for segmental paternal isodisomy. The critical region for isodisomy was refined to a 25 cM interval between D11S861 and D11S2071 which contained the IGF2, H19, and p57(KIP2) genes. In three cases isodisomy for 11q markers was detected but this did not extend further than 11q13-q21 suggesting that complete chromosome 11 disomy may not produce a BWS phenotype. The allele specific methylation status of the H19 gene was investigated in 80 sporadic BWS cases. All 13 cases with UPD tested displayed hypermethylation consistent with an excess of paternal H19 alleles. In addition, five of 63 (8%) cases with normal biparental inheritance had H19 hypermethylation consistent with an "imprinting centre" mutation (ICM) or "imprinting error" (IE) lesion. The phenotype of patients with putative ICM/IE mutations was variable and overlapped with that of non-UPD sporadic BWS cases with normal H19 methylation. However, exomphalos was significantly (p < 0.05) more common in the latter group. These findings may indicate differential effects on the expression of imprinted genes in chromosome 11p15 according to the precise molecular pathology. Analysis of H19 methylation is useful for the diagnosis of both UPD or altered imprinting in BWS and shows that a variety of molecular mechanisms may cause relaxation of IGF2 imprinting in BWS.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Abu-Amero, S, Monk, D, Frost, J, Preece, M, Stanier, P, Moore, G E (2008). The genetic aetiology of Silver-Russell syndrome. J. Med. Genet. 45: 193-199 [Abstract] [Full Text]  
• Grati, F R, Turolla, L, D'Ajello, P, Ruggeri, A, Miozzo, M, Bracalente, G, Baldo, D, Laurino, L, Boldorini, R, Frate, E, Surico, N, Larizza, L, Maggi, F, Simoni, G (2007). Chromosome 11 segmental paternal isodisomy in amniocytes from two fetuses with omphalocoele: new highlights on phenotype-genotype correlations in Beckwith-Wiedemann syndrome. J. Med. Genet. 44: 257-263 [Abstract] [Full Text]  
• Algar, E. M., St. Heaps, L., Darmanian, A., Dagar, V., Prawitt, D., Peters, G. B., Collins, F. (2007). Paternally Inherited Submicroscopic Duplication at 11p15.5 Implicates Insulin-like Growth Factor II in Overgrowth and Wilms' Tumorigenesis. Cancer Res. 67: 2360-2365 [Abstract] [Full Text]  
• Russo, S, Finelli, P, Recalcati, M P, Ferraiuolo, S, Cogliati, F, Dalla Bernardina, B, Tibiletti, M G, Agosti, M, Sala, M, Bonati, M T, Larizza, L (2006). Molecular and genomic characterisation of cryptic chromosomal alterations leading to paternal duplication of the 11p15.5 Beckwith-Wiedemann region.. J. Med. Genet. 43: e39-e39 [Abstract] [Full Text]  
• O'Neill, M. J. (2005). The influence of non-coding RNAs on allele-specific gene expression in mammals. Hum Mol Genet 14: R113-R120 [Abstract] [Full Text]  
• Dallosso, A. R., Hancock, A. L., Brown, K. W., Williams, A. C., Jackson, S., Malik, K. (2004). Genomic imprinting at the WT1 gene involves a novel coding transcript (AWT1) that shows deregulation in Wilms' tumours. Hum Mol Genet 13: 405-415 [Abstract] [Full Text]  
• Murrell, A., Heeson, S., Cooper, W. N., Douglas, E., Apostolidou, S., Moore, G. E., Maher, E. R., Reik, W. (2004). An association between variants in the IGF2 gene and Beckwith-Wiedemann syndrome: interaction between genotype and epigenotype. Hum Mol Genet 13: 247-255 [Abstract] [Full Text]  
• Maher, E R, Brueton, L A, Bowdin, S C, Luharia, A, Cooper, W, Cole, T R, Macdonald, F, Sampson, J R, Barratt, C L, Reik, W, Hawkins, M M (2003). Beckwith-Wiedemann syndrome and assisted reproduction technology (ART). J. Med. Genet. 40: 62-64 [Full Text]  
• Weksberg, R., Nishikawa, J., Caluseriu, O., Fei, Y.-L., Shuman, C., Wei, C., Steele, L., Cameron, J., Smith, A., Ambus, I., Li, M., Ray, P. N., Sadowski, P., Squire, J. (2001). Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1. Hum Mol Genet 10: 2989-3000 [Abstract] [Full Text]  
• Bliek, J., Maas, S. M., Ruijter, J. M., Hennekam, R. C.M., Alders, M., Westerveld, A., Mannens, M. M.A.M. (2001). Increased tumour risk for BWS patients correlates with aberrant H19 and not KCNQ1OT1 methylation: occurrence of KCNQ1OT1 hypomethylation in familial cases of BWS. Hum Mol Genet 10: 467-476 [Abstract] [Full Text]  
• Engel, J. R, Smallwood, A., Harper, A., Higgins, M. J, Oshimura, M., Reik, W., Schofield, P. N, Maher, E. R (2000). Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome. J. Med. Genet. 37: 921-926 [Abstract] [Full Text]  
• KOSAKI, K., KOSAKI, R., ROBINSON, W. P, CRAIGEN, W. J, SHAFFER, L. G, SATO, S., MATSUO, N. (2000). Diagnosis of maternal uniparental disomy of chromosome 7 with a methylation specific PCR assay. J. Med. Genet. 37: 19e-19 [Full Text]  
• CATCHPOOLE, D., SMALLWOOD, A. V, JOYCE, J. A, MURRELL, A., LAM, W., TANG, T., MUNROE, D., REIK, W., SCHOFIELD, P. N, MAHER, E. R (2000). Mutation analysis of H19 and NAP1L4 (hNAP2) candidate genes and IGF2 DMR2 in Beckwith-Wiedemann syndrome. J. Med. Genet. 37: 212-215 [Full Text]  
• Frevel, M. A. E., Sowerby, S. J., Petersen, G. B., Reeve, A. E. (1999). Methylation Sequencing Analysis Refines the Region of H19 Epimutation in Wilms Tumor. J. Biol. Chem. 274: 29331-29340 [Abstract] [Full Text]  
• Smilinich, N. J., Day, C. D., Fitzpatrick, G. V., Caldwell, G. M., Lossie, A. C., Cooper, P. R., Smallwood, A. C., Joyce, J. A., Schofield, P. N., Reik, W., Nicholls, R. D., Weksberg, R., Driscoll, D. J., Maher, E. R., Shows, T. B., Higgins, M. J. (1999). A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome. Proc. Natl. Acad. Sci. USA 96: 8064-8069 [Abstract] [Full Text]  
• Lam, W. W K, Hatada, I., Ohishi, S., Mukai, T., Joyce, J. A, Cole, T. R P, Donnai, D., Reik, W., Schofield, P. N, Maher, E. R (1999). Analysis of germline CDKN1C (p57KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation. J. Med. Genet. 36: 518-523 [Abstract] [Full Text]  
• Algar, E. M, Deeble, G. J, Smith, P. J (1999). CDKN1C expression in Beckwith-Wiedemann syndrome patients with allele imbalance. J. Med. Genet. 36: 524-531 [Abstract] [Full Text]  
• Falls, J. G., Pulford, D. J., Wylie, A. A., Jirtle, R. L. (1999). Genomic Imprinting: Implications for Human Disease. Am. J. Pathol. 154: 635-647 [Abstract] [Full Text]