Human Molecular Genetics Advance Access originally published online on January 8, 2008
Human Molecular Genetics 2008 17(8):1175-1183; doi:10.1093/hmg/ddn007
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Atypical Mowat–Wilson patient confirms the importance of the novel association between ZFHX1B/SIP1 and NuRD corepressor complex
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1 Laboratory of Molecular Biology (Celgen), Department of Human Genetics, KULeuven, B-3000 Leuven, Belgium 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 B-9000 Gent, Belgium 5 Department of Biochemistry, Faculty of Medicine and Health Sciences (UGent), B-9000 Gent, Belgium
* To whom correspondence should be addressed at: 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 16345916; Fax: +32 16345933; Email: danny.huylebroeck{at}med.kuleuven.be
Received September 25, 2007; 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Present address: Cell Biology and Histology (CYTO), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, B-1090 Jette, Belgium.