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| | Conserved domains present in MMSET variants (adapted from Keats et al., 2005). |
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| Description | Alternative splicing of exon 4 to 4a instead of 5 generates de MMSET III protein (273 amino acids, 32 kDa), due to the presence of an in-frame stop codon in exon 4a. Alternative splicing of exon 10 to 11 or 12 generates MMSET I (647 amino acids, 75kDa) or the full-length MMSET II (1365 amino acids, 155kDa) respectively, due to the presence of an in-frame stop codon in exon 11. A third transcript initiated within a middle intron of MMSET, encoding a mRNA comprising the 3'half of MMSET gene was identified and encodes a protein named RE-IIBP.
The long transcript, MMSET II, contains: 2 PWWP (proline-tryptophan-tryptophan-proline) domain, a HMG box (high mobility group), 4 PHD (plant-home domain)- type zinc finger motifs and a SET domain. MMSET I contains only a PWWP and a HMG domain and REIIBP, 2 PHD, a PWWP and a SET domain (Keats et al., 2005). |
| Expression | Widely expressed.
It is expressed preferentially in rapidly growing embryonic tissues, in a pattern corresponding to affected organs in WHS patients (Stec et al., 1998). |
| Localisation | Homogenous pattern within the nucleus, excluded from the nucleolus. |
| Function | Histone methyltransferase (Marango et al., 2007). |
| Entity | Multiple Myeloma (MM) |
| Disease | WHSC1 was identified as a gene involved in the t(4;14)(p16;q32) translocation present in approximately 15% to 20% of MM (Chesi et al., 1998). |
| Prognosis | This subtype of myeloma with t(4;14)(p16;q32) has a poor prognosis with frequent relapse after autologous stem-cell transplantation (Moreau et al., 2002; Chang et al., 2004). |
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| The t(4;14) Translocation Identifies MMSET as an oncogene in Multiple Myeloma. The gene rearrangement links the Eµ enhancer 5' to MMSET, driving transcription of MMSET from the telomeric-centromeric direction. The reciprocal translocation links an Ig enhancer 3' to the FGFR3 locus stimulating transcription in the centromeric-telomeric direction. |
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| Entity | Wolf-Hirschhorn syndrome (WHS) |
| Note | Wolf-Hirshhorn syndrome is caused by a partial deletion of chromosome 4p, particularly in the region of WHSC1 and WHSC2. About 87% of cases represent a de novo deletion, while about 13% are inherited from a parent with a chromosome translocation. |
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| 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 RS, Smith KD, Kuehl WM, Bergsagel PL. |
| Blood. 1998 Nov 1;92(9):3025-34. |
| PMID 9787135 |
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| 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 TJ, van Ommen GJ, de Boer PA, van Haeringen A, Moorman AF, Altherr MR, den Dunnen JT. |
| Hum Mol Genet. 1998 Jul;7(7):1071-82. |
| PMID 9618163 |
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| Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. |
| Moreau P, Facon T, Leleu X, Morineau N, Huyghe P, Harousseau JL, Bataille R, Avet-Loiseau H; Intergroupe Francophone du Myelome. |
| Blood. 2002 Sep 1;100(5):1579-83. |
| PMID 12176874 |
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| The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. |
| Chang H, Sloan S, Li D, Zhuang L, Yi QL, Chen CI, Reece D, Chun K, Keith Stewart A. |
| Br J Haematol. 2004 Apr;125(1):64-8. |
| PMID 15015970 |
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| Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients. |
| Keats JJ, Maxwell CA, Taylor BJ, Hendzel MJ, Chesi M, Bergsagel PL, Larratt LM, Mant MJ, Reiman T, Belch AR, Pilarski LM. |
| Blood. 2005 May 15;105(10):4060-9. Epub 2005 Jan 27. |
| PMID 15677557 |
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| The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. |
| Marango J, Shimoyama M, Nishio H, Meyer JA, Min DJ, Sirulnik A, Martinez-Martinez Y, Chesi M, Bergsagel PL, Zhou MM, Waxman S, Leibovitch BA, Walsh MJ, Licht JD. |
| Blood. 2008 Mar 15;111(6):3145-54. Epub 2007 Dec 21. |
| PMID 18156491 |
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