title: Atypical Mowat-Wilson patient confirms the importance of the novel association between ZFHX1B/SIP1 and NuRD corepressor complex.
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.
authors.affiliation: Laboratory of Molecular Biology (Celgen), Department of Human Genetics, KULeuven, B-3000 Leuven, Belgium.
authors.forename: Griet
authors.initials: G
authors.lastname: Verstappen
authors.forename: Leo A
authors.initials: LA
authors.lastname: van Grunsven
authors.forename: Christine
authors.initials: C
authors.lastname: Michiels
authors.forename: Tom
authors.initials: T
authors.lastname: Van de Putte
authors.forename: Jacob
authors.initials: J
authors.lastname: Souopgui
authors.forename: Jozef
authors.initials: J
authors.lastname: Van Damme
authors.forename: Eric
authors.initials: E
authors.lastname: Bellefroid
authors.forename: Joël
authors.initials: J
authors.lastname: Vandekerckhove
authors.forename: Danny
authors.initials: D
authors.lastname: Huylebroeck
mesh_terms: D000015:Abnormalities, Multiple / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D004265:DNA Helicases / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008607:Intellectual Disability / Q000378:metabolism*; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D013577:Syndrome; D014981:Xenopus
chemical_list: D001324:Autoantigens; C115323:CHD4 protein, human; D015820:Cadherins; C108381:GEMIN2 protein, human; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D000251:Adenosine Triphosphatases; D004265:DNA Helicases