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Gene Review

WHSC1  -  Wolf-Hirschhorn syndrome candidate 1

Homo sapiens

Synonyms: Histone-lysine N-methyltransferase NSD2, KIAA1090, MMSET, Multiple myeloma SET domain-containing protein, NSD2, ...
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Disease relevance of WHSC1


High impact information on WHSC1

  • Proliferation and MMSET-spike groups were characterized by significant overexpression of genes mapping to chromosome 1q, and both exhibited a poor prognosis relative to the other groups [3].
  • Quantitative reverse-transcription-polymerase chain reaction (RT-PCR) for proposed target genes on a panel of myeloma cell lines and purified plasma cells showed that only transcripts originating from the WHSC1/MMSET/NSD2 gene are uniformly dysregulated in all t(4;14)POS patients [1].
  • Cloning and localization of the Exon 4a/MMSET III splice variant, which contains the protein segment lost in the MB4-2 variant, identified a novel protein domain that prevents nucleolar localization [1].
  • Previous studies have revealed that that approximately 10% to 15% of multiple myelomas (MMs) are characterized by a reciprocal t(4;14)(p16;q32) translocation that activates expression of FGFR3 and creates an IGH/MMSET fusion transcript [4].
  • There is a promiscuous array of nonrandom chromosomal partners (and oncogenes), with the 3 most frequent partners (11q13 [cyclin D1]; 4p16 [FGFR3 and MMSET]; 16q23 [c-maf]) involved in nearly half of MM tumors [5].

Biological context of WHSC1


Anatomical context of WHSC1


Associations of WHSC1 with chemical compounds


Regulatory relationships of WHSC1

  • The t(4;14)(p16.3;q32) translocation that occurs uniquely in a subset of multiple myeloma tumors results in ectopic expression of wild-type FGFR3 and enhanced expression of MMSET, a gene that is homologous to the MLL gene that is involved in acute myeloid leukemias [13].
  • MMSET coexpression enhances HDAC1- and HDAC2-mediated repression in transcriptional reporter assays [14].

Other interactions of WHSC1

  • The smallest deletion detected in a WHS patient thus far includes two candidate genes, WHSC1 and WHSC2 [15].
  • WHSC1L1 is ubiquitously expressed and, like WHSC1, generates two major transcripts, a short (s-type) and a long (l-type) [9].
  • Given the homology to HRX/MLL1/ALL1 at 11q23 that is dysregulated by translocations in acute leukemia, we hypothesize that dysregulation of MMSET contributes to neoplastic transformation in MM with t(4;14) translocation [16].
  • A total of 127 genes were identified as being differentially expressed including MMSET and cyclin D2, which have been previously reported as being associated with this translocation [17].
  • Although a poor prognosis is linked with elevated MMSET expression, an extended follow-up period will be required to evaluate the significance of elevated TACC3 and p21 expression in this subgroup of MM [18].

Analytical, diagnostic and therapeutic context of WHSC1

  • A breakpoint-spanning PCR assay defined the distal breakpoint as disrupting the WHSC1 gene within intron 5, exactly after an AluJb repeat [19].


  1. Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients. Keats, J.J., Maxwell, C.A., Taylor, B.J., Hendzel, M.J., Chesi, M., Bergsagel, P.L., Larratt, L.M., Mant, M.J., Reiman, T., Belch, A.R., Pilarski, L.M. Blood (2005) [Pubmed]
  2. Identification of a novel proliferation-related protein, WHSC1 4a, in human gliomas. Li, J., Yin, C., Okamoto, H., Mushlin, H., Balgley, B.M., Lee, C.S., Yuan, K., Ikejiri, B., Glasker, S., Vortmeyer, A.O., Oldfield, E.H., Weil, R.J., Zhuang, Z. Neuro-oncology (2008) [Pubmed]
  3. The molecular classification of multiple myeloma. Zhan, F., Huang, Y., Colla, S., Stewart, J.P., Hanamura, I., Gupta, S., Epstein, J., Yaccoby, S., Sawyer, J., Burington, B., Anaissie, E., Hollmig, K., Pineda-Roman, M., Tricot, G., van Rhee, F., Walker, R., Zangari, M., Crowley, J., Barlogie, B., Shaughnessy, J.D. Blood (2006) [Pubmed]
  4. A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Santra, M., Zhan, F., Tian, E., Barlogie, B., Shaughnessy, J. Blood (2003) [Pubmed]
  5. Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Shaughnessy, J., Gabrea, A., Qi, Y., Brents, L., Zhan, F., Tian, E., Sawyer, J., Barlogie, B., Bergsagel, P.L., Kuehl, M. Blood (2001) [Pubmed]
  6. WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma. Stec, I., Wright, T.J., van Ommen, G.J., de Boer, P.A., van Haeringen, A., Moorman, A.F., Altherr, M.R., den Dunnen, J.T. Hum. Mol. Genet. (1998) [Pubmed]
  7. A unique mRNA initiated within a middle intron of WHSC1/MMSET encodes a DNA binding protein that suppresses human IL-5 transcription. Garlisi, C.G., Uss, A.S., Xiao, H., Tian, F., Sheridan, K.E., Wang, L., Motasim Billah M, n.u.l.l., Egan, R.W., Stranick, K.S., Umland, S.P. Am. J. Respir. Cell Mol. Biol. (2001) [Pubmed]
  8. Malignant hematological disorders in children with Wolf-Hirschhorn syndrome. Sharathkumar, A., Kirby, M., Freedman, M., Abdelhaleem, M., Chitayat, D., Teshima, I.E., Dror, Y. Am. J. Med. Genet. A (2003) [Pubmed]
  9. WHSC1L1, on human chromosome 8p11.2, closely resembles WHSC1 and maps to a duplicated region shared with 4p16.3. Stec, I., van Ommen, G.J., den Dunnen, J.T. Genomics (2001) [Pubmed]
  10. Detection of t(4;14)(p16.3;q32) chromosomal translocation in multiple myeloma by reverse transcription-polymerase chain reaction analysis of IGH-MMSET fusion transcripts. Malgeri, U., Baldini, L., Perfetti, V., Fabris, S., Vignarelli, M.C., Colombo, G., Lotti, V., Compasso, S., Bogni, S., Lombardi, L., Maiolo, A.T., Neri, A. Cancer Res. (2000) [Pubmed]
  11. Identification of ID-1 as a potential target gene of MMSET in multiple myeloma. Hudlebusch, H.R., Theilgaard-Mönch, K., Lodahl, M., Johnsen, H.E., Rasmussen, T. Br. J. Haematol. (2005) [Pubmed]
  12. Transcription repression activity is associated with the type I isoform of the MMSET gene involved in t(4;14) in multiple myeloma. Todoerti, K., Ronchetti, D., Agnelli, L., Castellani, S., Marelli, S., Deliliers, G.L., Zanella, A., Lombardi, L., Neri, A. Br. J. Haematol. (2005) [Pubmed]
  13. The enigma of ectopic expression of FGFR3 in multiple myeloma: a critical initiating event or just a target for mutational activation during tumor progression. Chesi, M., Bergsagel, P.L., Kuehl, W.M. Curr. Opin. Hematol. (2002) [Pubmed]
  14. The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Marango, J., Shimoyama, M., Nishio, H., Meyer, J.A., Min, D.J., Sirulnik, A., Martinez-Martinez, Y., Chesi, M., Bergsagel, P.L., Zhou, M.M., Waxman, S., Leibovitch, B.A., Walsh, M.J., Licht, J.D. Blood (2008) [Pubmed]
  15. Mild Wolf-Hirschhorn phenotype and partial GH deficiency in a patient with a 4p terminal deletion. Titomanlio, L., Romano, A., Conti, A., Genesio, R., Salerno, M., De Brasi, D., Nitsch, L., Del Giudice, E. Am. J. Med. Genet. A (2004) [Pubmed]
  16. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Chesi, M., Nardini, E., Lim, R.S., Smith, K.D., Kuehl, W.M., Bergsagel, P.L. Blood (1998) [Pubmed]
  17. A global expression-based analysis of the consequences of the t(4;14) translocation in myeloma. Dring, A.M., Davies, F.E., Fenton, J.A., Roddam, P.L., Scott, K., Gonzalez, D., Rollinson, S., Rawstron, A.C., Rees-Unwin, K.S., Li, C., Munshi, N.C., Anderson, K.C., Morgan, G.J. Clin. Cancer Res. (2004) [Pubmed]
  18. Correlation of TACC3, FGFR3, MMSET and p21 expression with the t(4;14)(p16.3;q32) in multiple myeloma. Stewart, J.P., Thompson, A., Santra, M., Barlogie, B., Lappin, T.R., Shaughnessy, J. Br. J. Haematol. (2004) [Pubmed]
  19. First known microdeletion within the Wolf-Hirschhorn syndrome critical region refines genotype-phenotype correlation. Rauch, A., Schellmoser, S., Kraus, C., Dörr, H.G., Trautmann, U., Altherr, M.R., Pfeiffer, R.A., Reis, A. Am. J. Med. Genet. (2001) [Pubmed]
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