Nature Genetics
15, 181 - 185 (1997)
doi:10.1038/ng0297-181
Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangementsMaxwell P. Lee1, Ren-JuHu Hu1, Laura A. Johnson1
& Andrew P. Feinberg1
1Departments of Medicine, Molecular Biology & Genetics, and Oncology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 1064, Baltimore, Maryland 21205, USA. Genomic imprinting is an epigenetic chromosomal modification in the gamete or zygote causing preferential expression of a specific parental allele in somatic cells of the offspring. We and others have identified three imprinted human genes on 11p15.5, IGF2 (refs 1-4), H19 (refs 1,5), and p57KIP2 (ref. 6), although the latter gene is separated by 700 kb from the other two, and it is unclear whether there are other imprinted genes within this large interval. We previously mapped an embryonal tumour suppressor gene to this region7, as well as five balanced germline chromosomal rearrangement breakpoints from patients with Beckwith-Wiedemann syndrome (BWS)8, a condition characterized by prenatal overgrowth and cancer. We isolated the upstream exons of the previously identified gene KVLQT1, which causes the familial cardiac defect long-QT (LQT) syndrome. We found that KVLQT1 spans much of the interval between p57KIP2 and IGF2, and that it is also imprinted. We demonstrated that the gene is disrupted by chromosomal rearrangements in BWS patients, as well as by a balanced chromosomal translocation in an embryonal rhabdoid tumour. Furthermore, the lack of parent-of-origin effect in LQT syndrome appears to be due to relative lack of imprinting in the affected tissue, cardiac muscle, representing a novel mechanism for variable penetrance of a human disease gene.
REFERENCES
- Rainier, S. et al. Relaxation of imprinted genes in human cancer. Nature 362, 747−749 (1993).
- Giannoukakis, N., Deal, C., Paquette, J., Goodyer, C.G. & Polychronakos, C. Parental genomic imprinting of the human IGF2 gene. Nature Genet. 4, 98−101 (1993).
- Ohlsson, R. et al. IGF2 is parentally imprinted during human embryogenesis and in the Beckwith-Wiedemann syndrome. Nature Genet. 4, 94−97 (1993).
- Ogawa, O. et al. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour. Nature 362, 749−751 (1993).
- Zhang, Y. & Tycko, B. Monoallelic expression of the human H19gene. Nature Genet 1, 40−44 (1992).
- Matsuoka, S. et al. Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor, p57KIP2, on chromosome 11p15. Proc. Natl. Acad. Sci. USA 93, 3026−3030 (1996).
- Koi, M. et al. Tumor cell growth arrest caused by subchromosomal transferable DNA fragments from human chromosome 11. Science 260, 361−364 (1993).
- Hoovers, J.M.N. et al. Multiple genetic loci within 11p15 defined by Beckwith-Wiedemann syndrome rearrangement breakpoints and subchromosomal transferable fragments. Proc. Natl. Acad. Sci. USA 92, 12456−12460 (1995).
- Feinberg, A.P. A developmental context for multiple genetic alterations in Wilms' tumor. J. Cell Sci. 18, 7−12 (1994).
- Schroeder, W.T. et al. Nonrandom loss of maternal chromosome 11 alleles in Wilms tumors. Am. J. Hum. Genet. 40, 413−420 (1987).
- Scrable, H. et al. A model for embryonal rhabdomyosarcoma tumorigenesis that involves genome imprinting. Proc. Natl. Acad. Sci. USA 86, 7480−7484 (1989).
- Steenman, M.J.C. et al. Loss of imprinting of IGF2is linked to reduced expression and abnormal methylation of H19 in Wilms' tumour. Nature Genet. 7, 433−439 (1994).
- Moulton, T. et al. Epigenetic lesions at the H19locus in Wilms' tumour patients. Nature Genet. 7, 440−447 (1994).
- 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. Nature Genet. 5, 143−150 (1993).
- Reik, W. et al. Allelic methylation of H19and IGF2in the Beckwith-Wiedemann syndrome. Hum. Mol. Genet. 3, 1297−1301 (1995).
- Reik, W. et al. Imprinting mutations in the Beckwith-Wiedemann syndrome suggested by an altered imprinting pattern in the IGF2-H19domain. Hum. Mol. Genet. 4, 2379−2385 (1995).
- Thompson, J.S., Reese, K.J., DeBaun, M.R., Perlman, E.J. & Feinberg, A.P. Reduced expression of the cyclin-dependent kinase inhibitor gene p57KIP2in Wilms tumor. Cancer Res. (in the press).
- Chung, W.Y., Yuan, L., Feng, L., Hensle, T. & Tycko, B. Chromosome 11p15.5 regional imprinting-comparative analysis of KIP2 and H19 in human tissues and Wilms tumors. Hum. Mol. Genet. 5, 1101−1108 (1996).
- Wang, Q. et al. Positional cloning of a novel potassium channel gene: KvLQT1mutations cause cardiac arrhythmias. Nature Genet. 12, 17−23 (1996).
- Mannens, M. et al. Parental imprinting of human chromosome region 11p15.3−pter involved in the Beckwith-Wiedemann Syndrome and various human neoplasia. Eur. J. Hum. Genet. 2, 3−23 (1994).
- Dittrich, B. et al. Imprint switching on human chromosome 15 may involve alternative transcripts of the SNRPNgene. Nature Genet. 14, 163−170 (1996).
- Vu, T.H. & Hoffman, A.R. Promoter-specific imprinting of the human insulin-like growth factor-II gene. Nature 371, 714−717 (1994).
- Hatada, H. et al. An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome. Nature Genet. 14, 171−173 (1996).
- Burn, T.C., Connors, T.D., Klinger, K.W. & Landes, G.M. Increased exon-trapping efficiency through modifications to the pSPL3 splicing vector. Gene 161, 183−187 (1995).
- Altshul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403−410 (1990).
- Orita, M., Iwahana, H., Kanazawa, H., Hayashi, K. & Sekiya, T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc. Natl. Acad. Sci. USA 86, 2766−2770 (1989).
- Barhanin, J., Lesage, F., Guillemare, E., Fink, M., Lazdunski, M. & Romey, G. KvLQT1 and IsK (minK) proteins associate to form the lks cardiac potassium current. Nature 384, 78−80 (1996).
- Sanguinetti, M.C. et al. Coassembly of KvLQT1 and minK (IsK) proteins to form cardiac lks potassium channel. Nature. 384, 80−83 (1996).
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