Download Gene Section WHSC1 (Wolf-Hirschhorn syndrome candidate 1) Atlas of Genetics and Cytogenetics

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WHSC1 (Wolf-Hirschhorn syndrome candidate 1)
Eva Martinez-Garcia, Jonathan D Licht
Feinberg School of Medicine, Northwestern University, Hematology/Oncology Division, 303 East Chicago
Avenue, Chicago, IL 60611-3008, USA (EMG, JDL)
Published in Atlas Database: November 2008
Online updated version : http://AtlasGeneticsOncology.org/Genes/WHSC1ID42809ch4p16.html
DOI: 10.4267/2042/44586
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
DNA/RNA
Other names: MMSET (Multiple Myeloma SET
domain), NSD2 (Nuclear SET domain-containing 2),
REIIBP, TRX5 (Protein trithorax-5), WHS
HGNC (Hugo): WHSC1
Location: 4p16.3
Local order: From the telomeric to centromeric end
(Chesi et al., 1998).
Description
Spans 120 Kb of genomic DNA and consists of 24
exons transcribed into a mRNA that undergoes
alternative splicing (Marango et al., 2007).
Transcription
Undergoes complex alternative splicing. Most primary
trancripts splice directly to exon 3, which
Conserved domains present in MMSET variants (adapted from Keats et al., 2005).
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10)
739
WHSC1 (Wolf-Hirschhorn syndrome candidate 1)
Martinez-Garcia E, Licht JD
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.
contains the proper translation initiation site, though
small fraction of transcripts retain upstream sequence
including exons 1 and 2 (Keats et al., 2005).
Implicated in
Protein
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).
Multiple Myeloma (MM)
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).
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.
References
Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel
PL. The t(4;14) translocation in myeloma dysregulates both
FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET
hybrid transcripts. Blood. 1998 Nov 1;92(9):3025-34
Expression
Stec I, Wright TJ, van Ommen GJ, de Boer PA, van Haeringen
A, Moorman AF, Altherr MR, den Dunnen JT. 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 Mol Genet. 1998 Jul;7(7):107182
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
Moreau P, Facon T, Leleu X, Morineau N, Huyghe P,
Harousseau JL, Bataille R, Avet-Loiseau H. Recurrent 14q32
translocations determine the prognosis of multiple myeloma,
especially in patients receiving intensive chemotherapy. Blood.
2002 Sep 1;100(5):1579-83
Homogenous pattern within the nucleus, excluded from
the nucleolus.
Function
Histone methyltransferase (Marango et al., 2007).
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10)
740
WHSC1 (Wolf-Hirschhorn syndrome candidate 1)
Martinez-Garcia E, Licht JD
Chang H, Sloan S, Li D, Zhuang L, Yi QL, Chen CI, Reece D,
Chun K, Keith Stewart A. The t(4;14) is associated with poor
prognosis in myeloma patients undergoing autologous stem
cell transplant. Br J Haematol. 2004 Apr;125(1):64-8
MM, Waxman S, Leibovitch BA, Walsh MJ, Licht JD. The
MMSET protein is a histone methyltransferase with
characteristics of a transcriptional corepressor. Blood. 2008
Mar 15;111(6):3145-54
Keats JJ, Maxwell CA, Taylor BJ, Hendzel MJ, Chesi M,
Bergsagel PL, Larratt LM, Mant MJ, Reiman T, Belch AR,
Pilarski LM. Overexpression of transcripts originating from the
MMSET locus characterizes all t(4;14)(p16;q32)-positive
multiple myeloma patients. Blood. 2005 May 15;105(10):4060-9
This article should be referenced as such:
Martinez-Garcia E, Licht JD. WHSC1 (Wolf-Hirschhorn
syndrome candidate 1). Atlas Genet Cytogenet Oncol
Haematol. 2009; 13(10):739-741.
Marango J, Shimoyama M, Nishio H, Meyer JA, Min DJ,
Sirulnik A, Martinez-Martinez Y, Chesi M, Bergsagel PL, Zhou
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10)
741