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Atypical Mowat-Wilson patient confirms the importance of the novel association between ZFHX1B/SIP1 and NuRD corepressor complex

Griet Verstappen, Leo A. van Grunsven, Christine Michiels, Tom Van de Putte, Jacob Souopgui, Jozef Van Damme UGent, Eric Bellefroid, Joël Vandekerckhove UGent and Danny Huylebroeck (2008) HUMAN MOLECULAR GENETICS. 17(8). p.1175-1183
abstract
Mutations in ZFHX1B cause Mowat-Wilson syndrome (MWS) but the precise mechanisms underlying the aberrant functions of mutant ZFHX1B proteins (also named Smad-interacting protein-1, SIP1) in patients are unknown. Using mass spectrometry analysis, we identified subunits of the NuRD corepressor complex in affinity-purified Zfhx1b complexes. We find that Zfhx1b associates with NuRD through its N-terminal domain, which contains a previously postulated NuRD interacting motif. Interestingly, this motif is substituted by an unrelated sequence in a recently described MWS patient. We show here that such aberrant ZFHX1B protein is unable to recruit NuRD subunits and displays reduced transcriptional repression activity on the XBMP4 gene promoter, a target of Zfhx1b. We further demonstrate that the NuRD component Mi-2 beta is involved in repression of the Zfhx1b target gene E-cadherin as well as in Zfhx1b-induced neural induction in animal caps from Xenopus embryos. Thus, NuRD and Zfhx1b functionally interact, and defective NuRD recruitment by mutant human ZFHX1B can be a MWS-causing mechanism. This is the first study providing mechanistic insight into the aberrant function of a single domain of the multi-domain protein ZFHX1B/SIP1 in human disease.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
keyword
HIRSCHSPRUNG-DISEASE, HISTONE DEACETYLASE, TRANSCRIPTIONAL REPRESSION, E-CADHERIN, SYNDROME PHENOTYPE, MISSENSE MUTATION, DNA-BINDING, XENOPUS, MENTAL RETARDATION SYNDROME, SMAD-INTERACTING PROTEIN-1
journal title
HUMAN MOLECULAR GENETICS
Hum. Mol. Genet.
volume
17
issue
8
pages
1175 - 1183
Web of Science type
Article
Web of Science id
000254708200012
JCR category
GENETICS & HEREDITY
JCR impact factor
7.249 (2008)
JCR rank
15/138 (2008)
JCR quartile
1 (2008)
ISSN
0964-6906
DOI
10.1093/hmg/ddn007
language
English
UGent publication?
yes
classification
A1
id
745339
handle
http://hdl.handle.net/1854/LU-745339
date created
2009-09-09 09:03:01
date last changed
2013-01-30 09:42:08
@article{745339,
  abstract     = {Mutations in ZFHX1B cause Mowat-Wilson syndrome (MWS) but the precise mechanisms underlying the aberrant functions of mutant ZFHX1B proteins (also named Smad-interacting protein-1, SIP1) in patients are unknown. Using mass spectrometry analysis, we identified subunits of the NuRD corepressor complex in affinity-purified Zfhx1b complexes. We find that Zfhx1b associates with NuRD through its N-terminal domain, which contains a previously postulated NuRD interacting motif. Interestingly, this motif is substituted by an unrelated sequence in a recently described MWS patient. We show here that such aberrant ZFHX1B protein is unable to recruit NuRD subunits and displays reduced transcriptional repression activity on the XBMP4 gene promoter, a target of Zfhx1b. We further demonstrate that the NuRD component Mi-2 beta is involved in repression of the Zfhx1b target gene E-cadherin as well as in Zfhx1b-induced neural induction in animal caps from Xenopus embryos. Thus, NuRD and Zfhx1b functionally interact, and defective NuRD recruitment by mutant human ZFHX1B can be a MWS-causing mechanism. This is the first study providing mechanistic insight into the aberrant function of a single domain of the multi-domain protein ZFHX1B/SIP1 in human disease.},
  author       = {Verstappen, Griet and van Grunsven, Leo A. and Michiels, Christine and Van de Putte, Tom and Souopgui, Jacob and Van Damme, Jozef and Bellefroid, Eric and Vandekerckhove, Jo{\"e}l and Huylebroeck, Danny},
  issn         = {0964-6906},
  journal      = {HUMAN MOLECULAR GENETICS},
  keyword      = {HIRSCHSPRUNG-DISEASE,HISTONE DEACETYLASE,TRANSCRIPTIONAL REPRESSION,E-CADHERIN,SYNDROME PHENOTYPE,MISSENSE MUTATION,DNA-BINDING,XENOPUS,MENTAL RETARDATION SYNDROME,SMAD-INTERACTING PROTEIN-1},
  language     = {eng},
  number       = {8},
  pages        = {1175--1183},
  title        = {Atypical Mowat-Wilson patient confirms the importance of the novel association between ZFHX1B/SIP1 and NuRD corepressor complex},
  url          = {http://dx.doi.org/10.1093/hmg/ddn007},
  volume       = {17},
  year         = {2008},
}

Chicago
Verstappen, Griet, Leo A. van Grunsven, Christine Michiels, Tom Van de Putte, Jacob Souopgui, Jozef Van Damme, Eric Bellefroid, Joël Vandekerckhove, and Danny Huylebroeck. 2008. “Atypical Mowat-Wilson Patient Confirms the Importance of the Novel Association Between ZFHX1B/SIP1 and NuRD Corepressor Complex.” Human Molecular Genetics 17 (8): 1175–1183.
APA
Verstappen, G., van Grunsven, L. A., Michiels, C., Van de Putte, T., Souopgui, J., Van Damme, J., Bellefroid, E., et al. (2008). Atypical Mowat-Wilson patient confirms the importance of the novel association between ZFHX1B/SIP1 and NuRD corepressor complex. HUMAN MOLECULAR GENETICS, 17(8), 1175–1183.
Vancouver
1.
Verstappen G, van Grunsven LA, Michiels C, Van de Putte T, Souopgui J, Van Damme J, et al. Atypical Mowat-Wilson patient confirms the importance of the novel association between ZFHX1B/SIP1 and NuRD corepressor complex. HUMAN MOLECULAR GENETICS. 2008;17(8):1175–83.
MLA
Verstappen, Griet, Leo A. van Grunsven, Christine Michiels, et al. “Atypical Mowat-Wilson Patient Confirms the Importance of the Novel Association Between ZFHX1B/SIP1 and NuRD Corepressor Complex.” HUMAN MOLECULAR GENETICS 17.8 (2008): 1175–1183. Print.