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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1998 Apr;62(4):824–833. doi: 10.1086/301806

Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database.

C Jeanpierre 1, E Denamur 1, I Henry 1, M O Cabanis 1, S Luce 1, A Cécille 1, J Elion 1, M Peuchmaur 1, C Loirat 1, P Niaudet 1, M C Gubler 1, C Junien 1
PMCID: PMC1377045  PMID: 9529364

Abstract

Constitutional mutations of the WT1 gene, encoding a zinc-finger transcription factor involved in renal and gonadal development, are found in most patients with Denys-Drash syndrome (DDS), or diffuse mesangial sclerosis (DMS) associated with pseudohermaphroditism and/or Wilms tumor (WT). Most mutations in DDS patients lie in exon 8 or exon 9, encoding zinc finger 2 or zinc finger 3, respectively, with a hot spot (R394W) in exon 9. We analyzed a series of 24 patients, 10 with isolated DMS (IDMS), 10 with DDS, and 4 with urogenital abnormalities and/or WT. We report WT1 heterozygous mutations in 16 patients, 4 of whom presented with IDMS. One male and two female IDMS patients with WT1 mutations underwent normal puberty. Two mutations associated with IDMS are different from those described in DDS patients. No WT1 mutations were detected in the six other IDMS patients, suggesting genetic heterogeneity of this disease. We analyzed genotype/phenotype correlations, on the basis of the constitution of a WT1 mutation database of 84 germ-line mutations, to compare the distribution and type of mutations, according to the different symptoms. This demonstrated (1) the association between mutations in exons 8 and 9 and DMS; (2) among patients with DMS, a higher frequency of exon 8 mutations among 46, XY patients with female phenotype than among 46,XY patients with sexual ambiguity or male phenotype; and (3) statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions.

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Selected References

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  1. Akasaka Y., Kikuchi H., Nagai T., Hiraoka N., Kato S., Hata J. A point mutation found in the WT1 gene in a sporadic Wilms' tumor without genitourinary abnormalities is identical with the most frequent point mutation in Denys-Drash syndrome. FEBS Lett. 1993 Feb 8;317(1-2):39–43. doi: 10.1016/0014-5793(93)81487-k. [DOI] [PubMed] [Google Scholar]
  2. Baird P. N., Santos A., Groves N., Jadresic L., Cowell J. K. Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome. Hum Mol Genet. 1992 Aug;1(5):301–305. doi: 10.1093/hmg/1.5.301. [DOI] [PubMed] [Google Scholar]
  3. Barbaux S., Niaudet P., Gubler M. C., Grünfeld J. P., Jaubert F., Kuttenn F., Fékété C. N., Souleyreau-Therville N., Thibaud E., Fellous M. Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet. 1997 Dec;17(4):467–470. doi: 10.1038/ng1297-467. [DOI] [PubMed] [Google Scholar]
  4. Bardeesy N., Zabel B., Schmitt K., Pelletier J. WT1 mutations associated with incomplete Denys-Drash syndrome define a domain predicted to behave in a dominant-negative fashion. Genomics. 1994 Jun;21(3):663–664. doi: 10.1006/geno.1994.1333. [DOI] [PubMed] [Google Scholar]
  5. Baylin S. B. Tying it all together: epigenetics, genetics, cell cycle, and cancer. Science. 1997 Sep 26;277(5334):1948–1949. doi: 10.1126/science.277.5334.1948. [DOI] [PubMed] [Google Scholar]
  6. Beaudet A. L., Tsui L. C. A suggested nomenclature for designating mutations. Hum Mutat. 1993;2(4):245–248. doi: 10.1002/humu.1380020402. [DOI] [PubMed] [Google Scholar]
  7. Bickmore W. A., Oghene K., Little M. H., Seawright A., van Heyningen V., Hastie N. D. Modulation of DNA binding specificity by alternative splicing of the Wilms tumor wt1 gene transcript. Science. 1992 Jul 10;257(5067):235–237. doi: 10.1126/science.1321494. [DOI] [PubMed] [Google Scholar]
  8. Coppes M. J., Campbell C. E., Williams B. R. The role of WT1 in Wilms tumorigenesis. FASEB J. 1993 Jul;7(10):886–895. doi: 10.1096/fasebj.7.10.8393819. [DOI] [PubMed] [Google Scholar]
  9. Coppes M. J., Liefers G. J., Higuchi M., Zinn A. B., Balfe J. W., Williams B. R. Inherited WT1 mutation in Denys-Drash syndrome. Cancer Res. 1992 Nov 1;52(21):6125–6128. [PubMed] [Google Scholar]
  10. Denys P., Malvaux P., Van Den Berghe H., Tanghe W., Proesmans W. Association d'un syndrome anatomo-pathologique de pseudohermaphrodisme masculin, d'une tumeur de Wilms, d'une nephropathie parenchymateuse et d'un mosaicisme XX/XY. Arch Fr Pediatr. 1967 Aug-Sep;24(7):729–739. [PubMed] [Google Scholar]
  11. Drash A., Sherman F., Hartmann W. H., Blizzard R. M. A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension, and degenerative renal disease. J Pediatr. 1970 Apr;76(4):585–593. doi: 10.1016/s0022-3476(70)80409-7. [DOI] [PubMed] [Google Scholar]
  12. Drummond I. A., Madden S. L., Rohwer-Nutter P., Bell G. I., Sukhatme V. P., Rauscher F. J., 3rd Repression of the insulin-like growth factor II gene by the Wilms tumor suppressor WT1. Science. 1992 Jul 31;257(5070):674–678. doi: 10.1126/science.1323141. [DOI] [PubMed] [Google Scholar]
  13. Drummond I. A., Rupprecht H. D., Rohwer-Nutter P., Lopez-Guisa J. M., Madden S. L., Rauscher F. J., 3rd, Sukhatme V. P. DNA recognition by splicing variants of the Wilms' tumor suppressor, WT1. Mol Cell Biol. 1994 Jun;14(6):3800–3809. doi: 10.1128/mcb.14.6.3800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Englert C., Vidal M., Maheswaran S., Ge Y., Ezzell R. M., Isselbacher K. J., Haber D. A. Truncated WT1 mutants alter the subnuclear localization of the wild-type protein. Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):11960–11964. doi: 10.1073/pnas.92.26.11960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Haber D. A., Sohn R. L., Buckler A. J., Pelletier J., Call K. M., Housman D. E. Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9618–9622. doi: 10.1073/pnas.88.21.9618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Habib R., Gubler M. C., Antignac C., Gagnadoux M. F. Diffuse mesangial sclerosis: a congenital glomerulopathy with nephrotic syndrome. Adv Nephrol Necker Hosp. 1993;22:43–57. [PubMed] [Google Scholar]
  17. Huff V. Genotype/phenotype correlations in Wilms' tumor. Med Pediatr Oncol. 1996 Nov;27(5):408–414. doi: 10.1002/(SICI)1096-911X(199611)27:5<408::AID-MPO4>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  18. Huff V., Jaffe N., Saunders G. F., Strong L. C., Villalba F., Ruteshouser E. C. WT1 exon 1 deletion/insertion mutations in Wilms tumor patients, associated with di- and trinucleotide repeats and deletion hotspot consensus sequences. Am J Hum Genet. 1995 Jan;56(1):84–90. [PMC free article] [PubMed] [Google Scholar]
  19. Jadresic L., Leake J., Gordon I., Dillon M. J., Grant D. B., Pritchard J., Risdon R. A., Barratt T. M. Clinicopathologic review of twelve children with nephropathy, Wilms tumor, and genital abnormalities (Drash syndrome). J Pediatr. 1990 Nov;117(5):717–725. doi: 10.1016/s0022-3476(05)83327-x. [DOI] [PubMed] [Google Scholar]
  20. Jeanpierre C., Béroud C., Niaudet P., Junien C. Software and database for the analysis of mutations in the human WT1 gene. Nucleic Acids Res. 1998 Jan 1;26(1):271–274. doi: 10.1093/nar/26.1.271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jinno Y., Yun K., Nishiwaki K., Kubota T., Ogawa O., Reeve A. E., Niikawa N. Mosaic and polymorphic imprinting of the WT1 gene in humans. Nat Genet. 1994 Mar;6(3):305–309. doi: 10.1038/ng0394-305. [DOI] [PubMed] [Google Scholar]
  22. Kaplinsky C., Ghahremani M., Frishberg Y., Rechavi G., Pelletier J. Familial Wilms' tumor associated with a WT1 zinc finger mutation. Genomics. 1996 Dec 15;38(3):451–453. doi: 10.1006/geno.1996.0655. [DOI] [PubMed] [Google Scholar]
  23. Kreidberg J. A., Sariola H., Loring J. M., Maeda M., Pelletier J., Housman D., Jaenisch R. WT-1 is required for early kidney development. Cell. 1993 Aug 27;74(4):679–691. doi: 10.1016/0092-8674(93)90515-r. [DOI] [PubMed] [Google Scholar]
  24. Larsson S. H., Charlieu J. P., Miyagawa K., Engelkamp D., Rassoulzadegan M., Ross A., Cuzin F., van Heyningen V., Hastie N. D. Subnuclear localization of WT1 in splicing or transcription factor domains is regulated by alternative splicing. Cell. 1995 May 5;81(3):391–401. doi: 10.1016/0092-8674(95)90392-5. [DOI] [PubMed] [Google Scholar]
  25. Little M. H., Prosser J., Condie A., Smith P. J., Van Heyningen V., Hastie N. D. Zinc finger point mutations within the WT1 gene in Wilms tumor patients. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4791–4795. doi: 10.1073/pnas.89.11.4791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Little M., Holmes G., Bickmore W., van Heyningen V., Hastie N., Wainwright B. DNA binding capacity of the WT1 protein is abolished by Denys-Drash syndrome WT1 point mutations. Hum Mol Genet. 1995 Mar;4(3):351–358. doi: 10.1093/hmg/4.3.351. [DOI] [PubMed] [Google Scholar]
  27. Little M., Wells C. A clinical overview of WT1 gene mutations. Hum Mutat. 1997;9(3):209–225. doi: 10.1002/(SICI)1098-1004(1997)9:3<209::AID-HUMU2>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  28. Mitsuya K., Sui H., Meguro M., Kugoh H., Jinno Y., Niikawa N., Oshimura M. Paternal expression of WT1 in human fibroblasts and lymphocytes. Hum Mol Genet. 1997 Dec;6(13):2243–2246. doi: 10.1093/hmg/6.13.2243. [DOI] [PubMed] [Google Scholar]
  29. Moffett P., Bruening W., Nakagama H., Bardeesy N., Housman D., Housman D. E., Pelletier J. Antagonism of WT1 activity by protein self-association. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11105–11109. doi: 10.1073/pnas.92.24.11105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nordenskjöld A., Fricke G., Anvret M. Absence of mutations in the WT1 gene in patients with XY gonadal dysgenesis. Hum Genet. 1995 Jul;96(1):102–104. doi: 10.1007/BF00214195. [DOI] [PubMed] [Google Scholar]
  31. Nordenskjöld A., Friedman E., Sandstedt B., Söderhäll S., Anvret M. Constitutional and somatic mutations in the WT1 gene in Wilms' tumor patients. Int J Cancer. 1995 Nov 15;63(4):516–522. doi: 10.1002/ijc.2910630410. [DOI] [PubMed] [Google Scholar]
  32. Ogawa O., Eccles M. R., Yun K., Mueller R. F., Holdaway M. D., Reeve A. E. A novel insertional mutation at the third zinc finger coding region of the WT1 gene in Denys-Drash syndrome. Hum Mol Genet. 1993 Feb;2(2):203–204. doi: 10.1093/hmg/2.2.203. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. 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]
  35. Renshaw J., King-Underwood L., Pritchard-Jones K. Differential splicing of exon 5 of the Wilms tumour (WTI) gene. Genes Chromosomes Cancer. 1997 Aug;19(4):256–266. doi: 10.1002/(sici)1098-2264(199708)19:4<256::aid-gcc8>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  36. Rupprecht H. D., Drummond I. A., Madden S. L., Rauscher F. J., 3rd, Sukhatme V. P. The Wilms' tumor suppressor gene WT1 is negatively autoregulated. J Biol Chem. 1994 Feb 25;269(8):6198–6206. [PubMed] [Google Scholar]
  37. Schmitt K., Zabel B., Tulzer G., Eitelberger F., Pelletier J. Nephropathy with Wilms tumour or gonadal dysgenesis: incomplete Denys-Drash syndrome or separate diseases? Eur J Pediatr. 1995 Jul;154(7):577–581. doi: 10.1007/BF02074838. [DOI] [PubMed] [Google Scholar]
  38. Schumacher V., Schneider S., Figge A., Wildhardt G., Harms D., Schmidt D., Weirich A., Ludwig R., Royer-Pokora B. Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal-predominant histology. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3972–3977. doi: 10.1073/pnas.94.8.3972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tadokoro K., Oki N., Sakai A., Fujii H., Ohshima A., Nagafuchi S., Inoue T., Yamada M. PCR detection of 9 polymorphisms in the WT1 gene. Hum Mol Genet. 1993 Dec;2(12):2205–2206. doi: 10.1093/hmg/2.12.2205. [DOI] [PubMed] [Google Scholar]
  40. Wang Z. Y., Madden S. L., Deuel T. F., Rauscher F. J., 3rd The Wilms' tumor gene product, WT1, represses transcription of the platelet-derived growth factor A-chain gene. J Biol Chem. 1992 Nov 5;267(31):21999–22002. [PubMed] [Google Scholar]
  41. Wang Z. Y., Qiu Q. Q., Deuel T. F. The Wilms' tumor gene product WT1 activates or suppresses transcription through separate functional domains. J Biol Chem. 1993 May 5;268(13):9172–9175. [PubMed] [Google Scholar]
  42. Wang Z. Y., Qiu Q. Q., Huang J., Gurrieri M., Deuel T. F. Products of alternatively spliced transcripts of the Wilms' tumor suppressor gene, wt1, have altered DNA binding specificity and regulate transcription in different ways. Oncogene. 1995 Feb 2;10(3):415–422. [PubMed] [Google Scholar]

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