Click here to close Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly. We suggest using a current version of Chrome, FireFox, or Safari.
XB-ART-37091
Hum Mol Genet April 15, 2008; 17 (8): 1175-83.

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

Verstappen G , van Grunsven LA , Michiels C , Van de Putte T , Souopgui J , Van Damme J , Bellefroid E , Vandekerckhove J , Huylebroeck D .


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-2beta 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.

PubMed ID: 18182442
Article link: Hum Mol Genet


Species referenced: Xenopus laevis
Genes referenced: bcl11b bcl6 bmp4 cdh1 cdh4 crhbp ctbp2 hdac2 ikzf1 mta2 ncam1 rbbp4 sall1 sox2 tp53 trim28 zeb2 zfpm1
GO keywords: embryo development [+]
Morpholinos: chd4 MO1

OMIMs: MOWAT-WILSON SYNDROME; MOWS

Article Images: [+] show captions