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Human Molecular Genetics Advance Access published online on January 8, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn007
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Griet Verstappen1,2,$, Leo A. van Grunsven1,2,6,$, Christine Michiels1,2, Tom Van de Putte1,2,7, Jacob Souopgui3, Jozef Van Damme4,5, Eric Bellefroid3, Joël Vandekerckhove4,5 and Danny Huylebroeck1,2,*

1 Laboratory of Molecular Biology (Celgen), Department of Human Genetics, KULeuven 2 Department of Molecular and Developmental Genetics (VIB11), VIB, B-3000 Leuven, Belgium 3 Laboratoire d'Embryologie Moléculaire, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, B-6041 Gosselies, Belgium 4 Department of Medical Protein Research (VIB9), VIB 5 Department of Biochemistry, Faculty of Medicine and Health Sciences (UGent), B-9000 Gent, Belgium. 6 Present addresses: Cell Biology and Histology (CYTO), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, B-1090 Jette, Belgium 7 Tigenix S.A., B-3001 Leuven, Belgium

* Author for correspondence: Danny Huylebroeck, Laboratory of Molecular Biology (Celgen), Department of Molecular and Developmental Genetics (VIB11) and Department of Human Genetics, KULeuven, Campus Gasthuisberg (Bldg. Ond&Nav1, box 812), Herestraat 49, B-3000 Leuven, Belgium Tel : +32 16 345916 Fax : +32 16 345933 E-mail: danny.huylebroeck{at}med.kuleuven.be

Received September 25, 2007; Revised January 7, 2008; Accepted January 7, 2008

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-2β 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.

$ Shared first authors


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