3hpj

Structural highlights

Disease

[WT1_HUMAN] Defects in WT1 are the cause of Frasier syndrome (FS) [MIM:136680]. FS is characterized by a slowly progressing nephropathy leading to renal failure in adolescence or early adulthood, male pseudohermaphroditism, and no Wilms tumor. As for histological findings of the kidneys, focal glomerular sclerosis is often observed. There is phenotypic overlap with Denys-Drash syndrome. Inheritance is autosomal dominant.^[1] Defects in WT1 are the cause of Wilms tumor 1 (WT1) [MIM:194070]. WT is an embryonal malignancy of the kidney that affects approximately 1 in 10'000 infants and young children. It occurs both in sporadic and hereditary forms.^{[2] [3] [4] [5]} Defects in WT1 are the cause of Denys-Drash syndrome (DDS) [MIM:194080]. DDS is a typical nephropathy characterized by diffuse mesangial sclerosis, genital abnormalities, and/or Wilms tumor. There is phenotypic overlap with WAGR syndrome and Frasier syndrome. Inheritance is autosomal dominant, but most cases are sporadic.^{[6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]} Defects in WT1 are the cause of nephrotic syndrome type 4 (NPHS4) [MIM:256370]. A renal disease characterized clinically by proteinuria, hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. Some affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure. Most patients with NPHS4 show diffuse mesangial sclerosis on renal biopsy, which is a pathologic entity characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen.^{[23] [24] [25] [26]} Defects in WT1 are a cause of Meacham syndrome (MEACHS) [MIM:608978]. Meacham syndrome is a rare sporadically occurring multiple malformation syndrome characterized by male pseudohermaphroditism with abnormal internal female genitalia comprising a uterus and double or septate vagina, complex congenital heart defect and diaphragmatic abnormalities.^[27] Note=A chromosomal aberration involving WT1 may be a cause of desmoplastic small round cell tumor (DSRCT). Translocation t(11;22)(p13;q12) with EWSR1. Defects in WT1 may be a cause of mesothelioma malignant (MESOM) [MIM:156240]. An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos.^[28] [B2MG_HUMAN] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:241600]. Affected individuals show marked reduction in serum concentrations of immunoglobulin and albumin, probably due to rapid degradation.^[29] Note=Beta-2-microglobulin may adopt the fibrillar configuration of amyloid in certain pathologic states. The capacity to assemble into amyloid fibrils is concentration dependent. Persistently high beta(2)-microglobulin serum levels lead to amyloidosis in patients on long-term hemodialysis.^{[30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42]}

Function

[1A02_HUMAN] Involved in the presentation of foreign antigens to the immune system. [WT1_HUMAN] Transcription factor that plays an important role in cellular development and cell survival. Regulates the expression of numerous target genes, including EPO. Plays an essential role for development of the urogenital system. Recognizes and binds to the DNA sequence 5'-CGCCCCCGC-3'. It has a tumor suppressor as well as an oncogenic role in tumor formation. Function may be isoform-specific: isoforms lacking the KTS motif may act as transcription factors. Isoforms containing the KTS motif may bind mRNA and play a role in mRNA metabolism or splicing. Isoform 1 has lower affinity for DNA, and can bind RNA.^{[43] [44]} [B2MG_HUMAN] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Beta-2 microglobulin 3D structures
• MHC 3D structures

References

1. ↑ Kohsaka T, Tagawa M, Takekoshi Y, Yanagisawa H, Tadokoro K, Yamada M. Exon 9 mutations in the WT1 gene, without influencing KTS splice isoforms, are also responsible for Frasier syndrome. Hum Mutat. 1999;14(6):466-70. PMID:10571943 doi:<466::AID-HUMU4>3.0.CO;2-6 10.1002/(SICI)1098-1004(199912)14:6<466::AID-HUMU4>3.0.CO;2-6
2. ↑ Little MH, Prosser J, Condie A, Smith PJ, Van Heyningen V, Hastie ND. Zinc finger point mutations within the WT1 gene in Wilms tumor patients. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4791-5. PMID:1317572
3. ↑ 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):3972-7. PMID:9108089
4. ↑ Jeanpierre C, Denamur E, Henry I, Cabanis MO, Luce S, Cecille A, Elion J, Peuchmaur M, Loirat C, Niaudet P, Gubler MC, Junien C. 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. Am J Hum Genet. 1998 Apr;62(4):824-33. PMID:9529364 doi:S0002-9297(07)60974-4
5. ↑ Royer-Pokora B, Beier M, Henzler M, Alam R, Schumacher V, Weirich A, Huff V. Twenty-four new cases of WT1 germline mutations and review of the literature: genotype/phenotype correlations for Wilms tumor development. Am J Med Genet A. 2004 Jun 15;127A(3):249-57. PMID:15150775 doi:10.1002/ajmg.a.30015
6. ↑ Jeanpierre C, Denamur E, Henry I, Cabanis MO, Luce S, Cecille A, Elion J, Peuchmaur M, Loirat C, Niaudet P, Gubler MC, Junien C. 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. Am J Hum Genet. 1998 Apr;62(4):824-33. PMID:9529364 doi:S0002-9297(07)60974-4
7. ↑ Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L, et al.. Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell. 1991 Oct 18;67(2):437-47. PMID:1655284
8. ↑ Bruening W, Bardeesy N, Silverman BL, Cohn RA, Machin GA, Aronson AJ, Housman D, Pelletier J. Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development. Nat Genet. 1992 May;1(2):144-8. PMID:1302008 doi:http://dx.doi.org/10.1038/ng0592-144
9. ↑ Baird PN, Santos A, Groves N, Jadresic L, Cowell JK. Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome. Hum Mol Genet. 1992 Aug;1(5):301-5. PMID:1338906
10. ↑ Little MH, Williamson KA, Mannens M, Kelsey A, Gosden C, Hastie ND, van Heyningen V. Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion. Hum Mol Genet. 1993 Mar;2(3):259-64. PMID:8388765
11. ↑ Baird PN, Cowell JK. A novel zinc finger mutation in a patient with Denys-Drash syndrome. Hum Mol Genet. 1993 Dec;2(12):2193-4. PMID:8111391
12. ↑ Tsuda M, Sakiyama T, Kitagawa T, Watanabe S, Watanabe T, Takahashi S, Kawaguchi H, Ito K. Molecular analysis of two Japanese cases of Denys-Drash syndrome. J Inherit Metab Dis. 1993;16(5):876-80. PMID:8295405
13. ↑ Clarkson PA, Davies HR, Williams DM, Chaudhary R, Hughes IA, Patterson MN. Mutational screening of the Wilms's tumour gene, WT1, in males with genital abnormalities. J Med Genet. 1993 Sep;30(9):767-72. PMID:8411073
14. ↑ Nordenskjold A, Friedman E, Anvret M. WT1 mutations in patients with Denys-Drash syndrome: a novel mutation in exon 8 and paternal allele origin. Hum Genet. 1994 Feb;93(2):115-20. PMID:8112732
15. ↑ Tsuda M, Sakiyama T, Owada M, Chiba Y. A newly identified exonic mutation of the WT1 gene in a patient with Denys-Drash syndrome. Acta Paediatr Jpn. 1996 Jun;38(3):265-6. PMID:8741319
16. ↑ Ghahremani M, Chan CB, Bistritzer T, Aladjem MM, Tieder M, Pelletier J. A novel mutation H373Y in the Wilms' tumor suppressor gene, WT1, associated with Denys-Drash syndrome. Hum Hered. 1996 Nov-Dec;46(6):336-8. PMID:8956030
17. ↑ Kikuchi H, Takata A, Akasaka Y, Fukuzawa R, Yoneyama H, Kurosawa Y, Honda M, Kamiyama Y, Hata J. Do intronic mutations affecting splicing of WT1 exon 9 cause Frasier syndrome? J Med Genet. 1998 Jan;35(1):45-8. PMID:9475094
18. ↑ Little M, Carman G, Donaldson E. Novel WT1 exon 9 mutation (D396Y) in a patient with early onset Denys Drash syndrome. Hum Mutat. 2000 Apr;15(4):389. PMID:10738002 doi:<389::AID-HUMU29>3.0.CO;2-E 10.1002/(SICI)1098-1004(200004)15:4<389::AID-HUMU29>3.0.CO;2-E
19. ↑ Takata A, Kikuchi H, Fukuzawa R, Ito S, Honda M, Hata J. Constitutional WT1 correlate with clinical features in children with progressive nephropathy. J Med Genet. 2000 Sep;37(9):698-701. PMID:11182928
20. ↑ Ohta S, Ozawa T, Izumino K, Sakuragawa N, Fuse H. A novel missense mutation of the Wt1 gene causing Denys-Drash syndrome with exceptionally mild renal manifestations. J Urol. 2000 Jun;163(6):1857-8. PMID:10799199
21. ↑ Swiatecka-Urban A, Mokrzycki MH, Kaskel F, Da Silva F, Denamur E. Novel WT1 mutation (C388Y) in a female child with Denys-Drash syndrome. Pediatr Nephrol. 2001 Aug;16(8):627-30. PMID:11519891
22. ↑ Hu M, Craig J, Howard N, Kan A, Chaitow J, Little D, Alexander SI. A novel mutation of WT1 exon 9 in a patient with Denys-Drash syndrome and pyloric stenosis. Pediatr Nephrol. 2004 Oct;19(10):1160-3. Epub 2004 Jul 28. PMID:15349765 doi:10.1007/s00467-004-1564-3
23. ↑ Jeanpierre C, Denamur E, Henry I, Cabanis MO, Luce S, Cecille A, Elion J, Peuchmaur M, Loirat C, Niaudet P, Gubler MC, Junien C. 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. Am J Hum Genet. 1998 Apr;62(4):824-33. PMID:9529364 doi:S0002-9297(07)60974-4
24. ↑ Takata A, Kikuchi H, Fukuzawa R, Ito S, Honda M, Hata J. Constitutional WT1 correlate with clinical features in children with progressive nephropathy. J Med Genet. 2000 Sep;37(9):698-701. PMID:11182928
25. ↑ Schumacher V, Scharer K, Wuhl E, Altrogge H, Bonzel KE, Guschmann M, Neuhaus TJ, Pollastro RM, Kuwertz-Broking E, Bulla M, Tondera AM, Mundel P, Helmchen U, Waldherr R, Weirich A, Royer-Pokora B. Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations. Kidney Int. 1998 Jun;53(6):1594-600. PMID:9607189 doi:10.1046/j.1523-1755.1998.00948.x
26. ↑ Ruf RG, Schultheiss M, Lichtenberger A, Karle SM, Zalewski I, Mucha B, Everding AS, Neuhaus T, Patzer L, Plank C, Haas JP, Ozaltin F, Imm A, Fuchshuber A, Bakkaloglu A, Hildebrandt F. Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome. Kidney Int. 2004 Aug;66(2):564-70. PMID:15253707 doi:10.1111/j.1523-1755.2004.00775.x
27. ↑ Suri M, Kelehan P, O'neill D, Vadeyar S, Grant J, Ahmed SF, Tolmie J, McCann E, Lam W, Smith S, Fitzpatrick D, Hastie ND, Reardon W. WT1 mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformations. Am J Med Genet A. 2007 Oct 1;143A(19):2312-20. PMID:17853480 doi:10.1002/ajmg.a.31924
28. ↑ Park S, Schalling M, Bernard A, Maheswaran S, Shipley GC, Roberts D, Fletcher J, Shipman R, Rheinwald J, Demetri G, et al.. The Wilms tumour gene WT1 is expressed in murine mesoderm-derived tissues and mutated in a human mesothelioma. Nat Genet. 1993 Aug;4(4):415-20. PMID:8401592 doi:http://dx.doi.org/10.1038/ng0893-415
29. ↑ Wani MA, Haynes LD, Kim J, Bronson CL, Chaudhury C, Mohanty S, Waldmann TA, Robinson JM, Anderson CL. Familial hypercatabolic hypoproteinemia caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant beta2-microglobulin gene. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5084-9. Epub 2006 Mar 20. PMID:16549777 doi:10.1073/pnas.0600548103
30. ↑ Gorevic PD, Munoz PC, Casey TT, DiRaimondo CR, Stone WJ, Prelli FC, Rodrigues MM, Poulik MD, Frangione B. Polymerization of intact beta 2-microglobulin in tissue causes amyloidosis in patients on chronic hemodialysis. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7908-12. PMID:3532124
31. ↑ Argiles A, Derancourt J, Jauregui-Adell J, Mion C, Demaille JG. Biochemical characterization of serum and urinary beta 2 microglobulin in end-stage renal disease patients. Nephrol Dial Transplant. 1992;7(11):1106-10. PMID:1336137
32. ↑ Momoi T, Suzuki M, Titani K, Hisanaga S, Ogawa H, Saito A. Amino acid sequence of a modified beta 2-microglobulin in renal failure patient urine and long-term dialysis patient blood. Clin Chim Acta. 1995 May 15;236(2):135-44. PMID:7554280
33. ↑ Cunningham BA, Wang JL, Berggard I, Peterson PA. The complete amino acid sequence of beta 2-microglobulin. Biochemistry. 1973 Nov 20;12(24):4811-22. PMID:4586824
34. ↑ Haag-Weber M, Mai B, Horl WH. Isolation of a granulocyte inhibitory protein from uraemic patients with homology of beta 2-microglobulin. Nephrol Dial Transplant. 1994;9(4):382-8. PMID:8084451
35. ↑ Trinh CH, Smith DP, Kalverda AP, Phillips SE, Radford SE. Crystal structure of monomeric human beta-2-microglobulin reveals clues to its amyloidogenic properties. Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):9771-6. Epub 2002 Jul 15. PMID:12119416 doi:10.1073/pnas.152337399
36. ↑ Stewart-Jones GB, McMichael AJ, Bell JI, Stuart DI, Jones EY. A structural basis for immunodominant human T cell receptor recognition. Nat Immunol. 2003 Jul;4(7):657-63. Epub 2003 Jun 8. PMID:12796775 doi:10.1038/ni942
37. ↑ Kihara M, Chatani E, Iwata K, Yamamoto K, Matsuura T, Nakagawa A, Naiki H, Goto Y. Conformation of amyloid fibrils of beta2-microglobulin probed by tryptophan mutagenesis. J Biol Chem. 2006 Oct 13;281(41):31061-9. Epub 2006 Aug 10. PMID:16901902 doi:10.1074/jbc.M605358200
38. ↑ Eakin CM, Berman AJ, Miranker AD. A native to amyloidogenic transition regulated by a backbone trigger. Nat Struct Mol Biol. 2006 Mar;13(3):202-8. Epub 2006 Feb 19. PMID:16491088 doi:10.1038/nsmb1068
39. ↑ Iwata K, Matsuura T, Sakurai K, Nakagawa A, Goto Y. High-resolution crystal structure of beta2-microglobulin formed at pH 7.0. J Biochem. 2007 Sep;142(3):413-9. Epub 2007 Jul 23. PMID:17646174 doi:10.1093/jb/mvm148
40. ↑ Ricagno S, Colombo M, de Rosa M, Sangiovanni E, Giorgetti S, Raimondi S, Bellotti V, Bolognesi M. DE loop mutations affect beta2-microglobulin stability and amyloid aggregation. Biochem Biophys Res Commun. 2008 Dec 5;377(1):146-50. Epub 2008 Oct 1. PMID:18835253 doi:S0006-291X(08)01866-4
41. ↑ Esposito G, Ricagno S, Corazza A, Rennella E, Gumral D, Mimmi MC, Betto E, Pucillo CE, Fogolari F, Viglino P, Raimondi S, Giorgetti S, Bolognesi B, Merlini G, Stoppini M, Bolognesi M, Bellotti V. The controlling roles of Trp60 and Trp95 in beta2-microglobulin function, folding and amyloid aggregation properties. J Mol Biol. 2008 May 9;378(4):887-97. Epub 2008 Mar 8. PMID:18395224 doi:10.1016/j.jmb.2008.03.002
42. ↑ Ricagno S, Raimondi S, Giorgetti S, Bellotti V, Bolognesi M. Human beta-2 microglobulin W60V mutant structure: Implications for stability and amyloid aggregation. Biochem Biophys Res Commun. 2009 Mar 13;380(3):543-7. Epub 2009 Jan 25. PMID:19284997 doi:10.1016/j.bbrc.2009.01.116
43. ↑ Weiss TC, Romaniuk PJ. Contribution of individual amino acids to the RNA binding activity of the Wilms' tumor suppressor protein WT1. Biochemistry. 2009 Jan 13;48(1):148-55. doi: 10.1021/bi801586a. PMID:19123921 doi:10.1021/bi801586a
44. ↑ Rivera MN, Kim WJ, Wells J, Stone A, Burger A, Coffman EJ, Zhang J, Haber DA. The tumor suppressor WTX shuttles to the nucleus and modulates WT1 activity. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8338-43. doi:, 10.1073/pnas.0811349106. Epub 2009 May 4. PMID:19416806 doi:10.1073/pnas.0811349106
45. ↑ Borbulevych OY, Do P, Baker BM. Structures of native and affinity-enhanced WT1 epitopes bound to HLA-A*0201: implications for WT1-based cancer therapeutics. Mol Immunol. 2010 Sep;47(15):2519-24. Epub 2010 Jul 8. PMID:20619457 doi:10.1016/j.molimm.2010.06.005