Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1992 Dec;51(6):1286–1294.

Submicroscopic deletions at the WAGR locus, revealed by nonradioactive in situ hybridization.

J A Fantes 1, W A Bickmore 1, J M Fletcher 1, F Ballesta 1, I M Hanson 1, V van Heyningen 1
PMCID: PMC1682907  PMID: 1334370

Abstract

Fluorescence in situ hybridization (FISH) with biotin-labeled probes mapping to 11p13 has been used for the molecular analysis of deletions of the WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation) locus. We have detected a submicroscopic 11p13 deletion in a child with inherited aniridia who subsequently presented with Wilms tumor in a horseshoe kidney, only revealed at surgery. The mother, who has aniridia, was also found to carry a deletion including both the aniridia candidate gene (AN2) and the Wilms tumor predisposition gene (WT1). This is therefore a rare case of an inherited WAGR deletion. Wilms tumor has so far only been associated with sporadic de novo aniridia cases. We have shown that a cosmid probe for a candidate aniridia gene, homologous to the mouse Pax-6 gene, is deleted in cell lines from aniridia patients with previously characterized deletions at 11p13, while another cosmid marker mapping between two aniridia-associated translocation breakpoints (and hence a second candidate marker) is present on both chromosomes. These results support the Pax-6 homologue as a strong candidate for the AN2 gene. FISH with cosmid probes has proved to be a fast and reliable technique for the molecular analysis of deletions. It can be used with limited amounts of material and has strong potential for clinical applications.

Full text

PDF
1289

Images in this article

1290Figure 2
on p.1290
1291Figure 3
on p.1291

Selected References

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

  1. Bickmore W. A., Porteous D. J., Christie S., Seawright A., Fletcher J. M., Maule J. C., Couillin P., Junien C., Hastie N. D., van Heyningen V. CpG islands surround a DNA segment located between translocation breakpoints associated with genitourinary dysplasia and aniridia. Genomics. 1989 Nov;5(4):685–693. doi: 10.1016/0888-7543(89)90109-2. [DOI] [PubMed] [Google Scholar]
  2. Bickmore W., Christie S., van Heyningen V., Hastie N. D., Porteous D. J. Hitch-hiking from HRAS1 to the WAGR locus with CMGT markers. Nucleic Acids Res. 1988 Jan 11;16(1):51–60. doi: 10.1093/nar/16.1.51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Breslow N., Beckwith J. B., Ciol M., Sharples K. Age distribution of Wilms' tumor: report from the National Wilms' Tumor Study. Cancer Res. 1988 Mar 15;48(6):1653–1657. [PubMed] [Google Scholar]
  4. Call K. M., Glaser T., Ito C. Y., Buckler A. J., Pelletier J., Haber D. A., Rose E. A., Kral A., Yeger H., Lewis W. H. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell. 1990 Feb 9;60(3):509–520. doi: 10.1016/0092-8674(90)90601-a. [DOI] [PubMed] [Google Scholar]
  5. Compton D. A., Weil M. M., Jones C., Riccardi V. M., Strong L. C., Saunders G. F. Long range physical map of the Wilms' tumor-aniridia region on human chromosome 11. Cell. 1988 Dec 2;55(5):827–836. doi: 10.1016/0092-8674(88)90138-9. [DOI] [PubMed] [Google Scholar]
  6. Davis L. M., Stallard R., Thomas G. H., Couillin P., Junien C., Nowak N. J., Shows T. B. Two anonymous DNA segments distinguish the Wilms' tumor and aniridia loci. Science. 1988 Aug 12;241(4867):840–842. doi: 10.1126/science.2841760. [DOI] [PubMed] [Google Scholar]
  7. Francke U., Holmes L. B., Atkins L., Riccardi V. M. Aniridia-Wilms' tumor association: evidence for specific deletion of 11p13. Cytogenet Cell Genet. 1979;24(3):185–192. doi: 10.1159/000131375. [DOI] [PubMed] [Google Scholar]
  8. Gessler M., Poustka A., Cavenee W., Neve R. L., Orkin S. H., Bruns G. A. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature. 1990 Feb 22;343(6260):774–778. doi: 10.1038/343774a0. [DOI] [PubMed] [Google Scholar]
  9. Gessler M., Simola K. O., Bruns G. A. Cloning of breakpoints of a chromosome translocation identifies the AN2 locus. Science. 1989 Jun 30;244(4912):1575–1578. doi: 10.1126/science.2544995. [DOI] [PubMed] [Google Scholar]
  10. Gessler M., Thomas G. H., Couillin P., Junien C., McGillivray B. C., Hayden M., Jaschek G., Bruns G. A. A deletion map of the WAGR region on chromosome 11. Am J Hum Genet. 1989 Apr;44(4):486–495. [PMC free article] [PubMed] [Google Scholar]
  11. Glaser T., Lane J., Housman D. A mouse model of the aniridia-Wilms tumor deletion syndrome. Science. 1990 Nov 9;250(4982):823–827. doi: 10.1126/science.2173141. [DOI] [PubMed] [Google Scholar]
  12. Glaser T., Lewis W. H., Bruns G. A., Watkins P. C., Rogler C. E., Shows T. B., Powers V. E., Willard H. F., Goguen J. M., Simola K. O. The beta-subunit of follicle-stimulating hormone is deleted in patients with aniridia and Wilms' tumour, allowing a further definition of the WAGR locus. 1986 Jun 26-Jul 2Nature. 321(6073):882–887. doi: 10.1038/321882a0. [DOI] [PubMed] [Google Scholar]
  13. Grundy P., Koufos A., Morgan K., Li F. P., Meadows A. T., Cavenee W. K. Familial predisposition to Wilms' tumour does not map to the short arm of chromosome 11. Nature. 1988 Nov 24;336(6197):374–376. doi: 10.1038/336374a0. [DOI] [PubMed] [Google Scholar]
  14. Hill R. E., Favor J., Hogan B. L., Ton C. C., Saunders G. F., Hanson I. M., Prosser J., Jordan T., Hastie N. D., van Heyningen V. Mouse small eye results from mutations in a paired-like homeobox-containing gene. Nature. 1991 Dec 19;354(6354):522–525. doi: 10.1038/354522a0. [DOI] [PubMed] [Google Scholar]
  15. Hoovers J. M., Mannens M., John R., Bliek J., van Heyningen V., Porteous D. J., Leschot N. J., Westerveld A., Little P. F. High-resolution localization of 69 potential human zinc finger protein genes: a number are clustered. Genomics. 1992 Feb;12(2):254–263. doi: 10.1016/0888-7543(92)90372-y. [DOI] [PubMed] [Google Scholar]
  16. Huff V., Compton D. A., Chao L. Y., Strong L. C., Geiser C. F., Saunders G. F. Lack of linkage of familial Wilms' tumour to chromosomal band 11p13. Nature. 1988 Nov 24;336(6197):377–378. doi: 10.1038/336377a0. [DOI] [PubMed] [Google Scholar]
  17. Huff V., Meadows A., Riccardi V. M., Strong L. C., Saunders G. F. Parental origin of de novo constitutional deletions of chromosomal band 11p13. Am J Hum Genet. 1990 Jul;47(1):155–160. [PMC free article] [PubMed] [Google Scholar]
  18. Kuwano A., Ledbetter S. A., Dobyns W. B., Emanuel B. S., Ledbetter D. H. Detection of deletions and cryptic translocations in Miller-Dieker syndrome by in situ hybridization. Am J Hum Genet. 1991 Oct;49(4):707–714. [PMC free article] [PubMed] [Google Scholar]
  19. Landegent J. E., Jansen in de Wal N., Dirks R. W., Baao F., van der Ploeg M. Use of whole cosmid cloned genomic sequences for chromosomal localization by non-radioactive in situ hybridization. Hum Genet. 1987 Dec;77(4):366–370. doi: 10.1007/BF00291428. [DOI] [PubMed] [Google Scholar]
  20. Langer-Safer P. R., Levine M., Ward D. C. Immunological method for mapping genes on Drosophila polytene chromosomes. Proc Natl Acad Sci U S A. 1982 Jul;79(14):4381–4385. doi: 10.1073/pnas.79.14.4381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lewis W. H., Yeger H., Bonetta L., Chan H. S., Kang J., Junien C., Cowell J., Jones C., Dafoe L. A. Homozygous deletion of a DNA marker from chromosome 11p13 in sporadic Wilms tumor. Genomics. 1988 Jul;3(1):25–31. doi: 10.1016/0888-7543(88)90154-1. [DOI] [PubMed] [Google Scholar]
  22. Li F. P., Williams W. R., Gimbrere K., Flamant F., Green D. M., Meadows A. T. Heritable fraction of unilateral Wilms tumor. Pediatrics. 1988 Jan;81(1):147–149. [PubMed] [Google Scholar]
  23. Lichter P., Tang C. J., Call K., Hermanson G., Evans G. A., Housman D., Ward D. C. High-resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones. Science. 1990 Jan 5;247(4938):64–69. doi: 10.1126/science.2294592. [DOI] [PubMed] [Google Scholar]
  24. Lux S. E., Tse W. T., Menninger J. C., John K. M., Harris P., Shalev O., Chilcote R. R., Marchesi S. L., Watkins P. C., Bennett V. Hereditary spherocytosis associated with deletion of human erythrocyte ankyrin gene on chromosome 8. Nature. 1990 Jun 21;345(6277):736–739. doi: 10.1038/345736a0. [DOI] [PubMed] [Google Scholar]
  25. MILLER R. W., FRAUMENI J. F., Jr, MANNING M. D. ASSOCIATION OF WILMS'S TUMOR WITH ANIRIDIA, HEMIHYPERTROPHY AND OTHER CONGENITAL MALFORMATIONS. N Engl J Med. 1964 Apr 30;270:922–927. doi: 10.1056/NEJM196404302701802. [DOI] [PubMed] [Google Scholar]
  26. Mannens M., Hoovers J. M., Bleeker-Wagemakers E. M., Redeker E., Bliek J., Overbeeke-Melkert M., Saunders G., Williams B., van Heyningen V., Junien C. The distal region of 11p13 and associated genetic diseases. Genomics. 1991 Oct;11(2):284–293. doi: 10.1016/0888-7543(91)90134-z. [DOI] [PubMed] [Google Scholar]
  27. Pelletier J., Bruening W., Kashtan C. E., Mauer S. M., Manivel J. C., Striegel J. E., Houghton D. C., Junien C., Habib R., Fouser L. Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell. 1991 Oct 18;67(2):437–447. doi: 10.1016/0092-8674(91)90194-4. [DOI] [PubMed] [Google Scholar]
  28. Pelletier J., Bruening W., Li F. P., Haber D. A., Glaser T., Housman D. E. WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumour. Nature. 1991 Oct 3;353(6343):431–434. doi: 10.1038/353431a0. [DOI] [PubMed] [Google Scholar]
  29. Pinkel D., Straume T., Gray J. W. Cytogenetic analysis using quantitative, high-sensitivity, fluorescence hybridization. Proc Natl Acad Sci U S A. 1986 May;83(9):2934–2938. doi: 10.1073/pnas.83.9.2934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Porteous D. J., Bickmore W., Christie S., Boyd P. A., Cranston G., Fletcher J. M., Gosden J. R., Rout D., Seawright A., Simola K. O. HRAS1-selected chromosome transfer generates markers that colocalize aniridia- and genitourinary dysplasia-associated translocation breakpoints and the Wilms tumor gene within band 11p13. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5355–5359. doi: 10.1073/pnas.84.15.5355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pritchard-Jones K., Fleming S., Davidson D., Bickmore W., Porteous D., Gosden C., Bard J., Buckler A., Pelletier J., Housman D. The candidate Wilms' tumour gene is involved in genitourinary development. Nature. 1990 Jul 12;346(6280):194–197. doi: 10.1038/346194a0. [DOI] [PubMed] [Google Scholar]
  32. Ried T., Mahler V., Vogt P., Blonden L., van Ommen G. J., Cremer T., Cremer M. Direct carrier detection by in situ suppression hybridization with cosmid clones of the Duchenne/Becker muscular dystrophy locus. Hum Genet. 1990 Oct;85(6):581–586. doi: 10.1007/BF00193578. [DOI] [PubMed] [Google Scholar]
  33. Royer-Pokora B., Ragg S., Heckl-Ostreicher B., Held M., Loos U., Call K., Glaser T., Housman D., Saunders G., Zabel B. Direct pulsed field gel electrophoresis of Wilms' tumors shows that DNA deletions in 11p13 are rare. Genes Chromosomes Cancer. 1991 Mar;3(2):89–100. doi: 10.1002/gcc.2870030203. [DOI] [PubMed] [Google Scholar]
  34. Seawright A., Fletcher J. M., Fantes J. A., Morrison H., Porteous D. J., Li S. S., Hastie N. D., Van Heyningen V. Analysis of WAGR deletions and related translocations with gene-specific DNA probes, using FACS-selected cell hybrids. Somat Cell Mol Genet. 1988 Jan;14(1):21–30. doi: 10.1007/BF01535046. [DOI] [PubMed] [Google Scholar]
  35. Simola K. O., Knuutila S., Kaitila I., Pirkola A., Pohja P. Familial aniridia and translocation t(4;11)(q22;p13) without Wilms' tumor. Hum Genet. 1983;63(2):158–161. doi: 10.1007/BF00291536. [DOI] [PubMed] [Google Scholar]
  36. Spurr N. K., Feder J., Bodmer W. F., Goodfellow P. N., Solomon E., Cavalli-Sforza L. L. Chromosomal assignment of seven human genomic DNA sequences associated with restriction fragment length polymorphisms. Ann Hum Genet. 1986 May;50(Pt 2):145–152. doi: 10.1111/j.1469-1809.1986.tb01033.x. [DOI] [PubMed] [Google Scholar]
  37. Ton C. C., Hirvonen H., Miwa H., Weil M. M., Monaghan P., Jordan T., van Heyningen V., Hastie N. D., Meijers-Heijboer H., Drechsler M. Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region. Cell. 1991 Dec 20;67(6):1059–1074. doi: 10.1016/0092-8674(91)90284-6. [DOI] [PubMed] [Google Scholar]
  38. Van Heyningen V., Hastie N. D. Wilms' tumour: reconciling genetics and biology. Trends Genet. 1992 Jan;8(1):16–21. doi: 10.1016/0168-9525(92)90019-z. [DOI] [PubMed] [Google Scholar]
  39. van Heyningen V., Bickmore W. A., Seawright A., Fletcher J. M., Maule J., Fekete G., Gessler M., Bruns G. A., Huerre-Jeanpierre C., Junien C. Role for the Wilms tumor gene in genital development? Proc Natl Acad Sci U S A. 1990 Jul;87(14):5383–5386. doi: 10.1073/pnas.87.14.5383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. van Heyningen V., Boyd P. A., Seawright A., Fletcher J. M., Fantes J. A., Buckton K. E., Spowart G., Porteous D. J., Hill R. E., Newton M. S. Molecular analysis of chromosome 11 deletions in aniridia-Wilms tumor syndrome. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8592–8596. doi: 10.1073/pnas.82.24.8592. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES