WHSC1
MIM.602952 4p16.3
MMSET is expressed ubiquitously in early development and its deletion is associated with the malformation syndrome called Wolf-Hirschhorn syndrome.
Stec et al. (1998) described a novel developmental gene, two-thirds of which maps in the distal part of the WHS critical region. They designated the gene WHSC1 (Wolf-Hirschhorn syndrome candidate-1).
The WHSC1 gene was identified initially through its high similarity to the translation product of an expressed sequence tag, located in the 165-kb WHCR, with the SET domain (MIM.600960) of the Drosophila protein ASH1 (MIM.607999). The SET domain is found in proteins that are involved in embryonic development.
The 25-exon WHSC1 gene was found to be expressed ubiquitously in early development and to undergo complex alternative splicing and differential polyadenylation.
It encodes a 136-kD protein containing 4 domains present in other developmental proteins: a PWWP domain, an HMG box, a SET domain also found in the Drosophila dysmorphy gene ash-encoded protein, and a PHD-type zinc finger.
It is expressed preferentially in rapidly growing embryonic tissues, in a pattern corresponding to affected organs in WHS patients.
Pathology
Wolf-Hirschhorn syndrome (WHS; MIM.194190) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4 (4p16.3).
- The shortest region of overlap of the deletions observed in Wolf-Hirschhorn syndrome (WHS; MIM.194190) patients, the WHS critical region, has been confined to a region of 165 kb (Wright et al., 1997). This region was sequenced completely during the search for the Huntington disease gene (Baxendale et al., 1993).
- The nature of the protein motifs, the expression pattern, and its mapping to the critical region led Stec et al. (1998) to propose WHSC1 as a good candidate gene to be responsible for many of the phenotypic features of WHS.
t(4;14)(p16.3;q32.3) translocation
- MMSET is involved in the t(4;14) (p16;q32) chromosomal translocation, which is the second most common translocation in multiple myeloma (MM) and is associated with the worst prognosis.
- The t(4;14)(p16.3;q32.3) translocations described in a significant fraction of multiple myelomas have breakpoints located less than 100 kb centromeric of the FGFR3 gene (134934) on 4p16.3.
- At least 3 of the breakpoints merged the immunoglobulin heavy-chain gene (IGHG1; MIM.147100) on chromosome 14 with the WHSC1 gene.
- This fusion of genes and their untimely expression in the myeloid lineage driven from the 5-prime IgH enhancer may indicate that WHSC1-encoded proteins are involved in the clinical heterogeneity of multiple myeloma.
MMSET expression has been shown to promote cellular adhesion, clonogenic growth and tumorigenicity in multiple myeloma.
MMSET expression has been shown to increase with ascending tumor proliferation activity in glioblastoma multiforme.
MMSET could be implicated in tumor emergence and/or progression. MMSET is associated with tumor aggressiveness or prognosis in several types of cancers.
MMSET potentially acts as a pathogenic agent in many cancers.
WHSC1 (MMSET) is overexpressed in cancers (#19121287#)
REFERENCES
MMSET is overexpressed in cancers: link with tumor aggressiveness. Kassambara A, Klein B, Moreaux J. Biochem Biophys Res Commun. 2009 Feb 20;379(4):840-5. PMID: #19121287#
Baxendale, S.; MacDonald, M. E.; Mott, R.; Francis, F.; Lin, C.; Kirby, S. F.; James, M.; Zehetner, G.; Hummerich, H.; Valdes, J.; Collins, F. S.; Deaven, L. J.; Gusella, J. F.; Lehrach, H.; Bates, G. P. : A cosmid contig and high resolution restriction map of the 2 megabase region containing the Huntington’s disease gene. Nature Genet. 4: 181-186, 1993. PubMed ID : #8348156#
Chesi, M.; Nardini, E.; Brents, L. A.; Schrock, E.; Ried, T.; Kuehl, W. M.; Bergsagel, P. L. : Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nature Genet. 16: 260-264, 1997. PubMed ID : #9207791#
Richelda, R.; Ronchetti, D.; Baldini, L.; Cro, L.; Viggiano, L.; Marzella, R.; Rocchi, M.; Otsuki, T.; Lombardi, L.; Maiolo, A. T.; Neri, A. : A novel chromosomal translocation t(4;14)(p16.3;q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene. Blood 90: 4062-4070, 1997. PubMed ID : #9354676#
Stec, I.; Wright, T. J.; van Ommen, G.-J. B.; de Boer, P. A. J.; van Haeringen, A.; Moorman, A. F. M.; Altherr, M. R.; den Dunnen, J. T. : 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. Hum. Molec. Genet. 7: 1071-1082, 1998. PubMed ID : #9618163#
Wright, T. J.; Ricke, D. O.; Denison, K.; Abmayr, S.; Cotter, P. D.; Hirschhorn, K.; Keinanen, M.; McDonald-McGinn, D.; Somer, M.; Spinner, N.; Yang-Feng, T.; Zackai, E.; Altherr, M. R. : A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region. Hum. Molec. Genet. 6: 317-324, 1997. PubMed ID : #9063753#