Home News About Us Contact Contributors Disclaimer Privacy Policy Help FAQ

Quick Search
My eDoc
Support Wiki
Direct access to
document ID:

          Document History for Document ID 473310

Back to latest document version
Document Version Version Comment Date Status
473310.0 Automatic journal name synchronization 27.03.2010 20:15 Released

ID: 473310.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Point mutations in GLI3 lead to misregulation of its subcellular localization
Authors:Krauß, Sybille; So, Joyce; Hambrock, Melanie; Köhler, Andrea; Kunath, Melanie; Scharff, Constance; Wessling, Martina; Grzeschik, Karl-Heinz; Schneider, Rainer; Schweiger, Susann
Date of Publication (YYYY-MM-DD):2009-10-15
Title of Journal:PLoS ONE
Start Page:e7471
End Page:e7471
Copyright:© 2009 Krauß et al
Review Status:not specified
Audience:Experts Only
Abstract / Description:Background
Mutations in the transcription factor GLI3, a downstream target of Sonic Hedgehog (SHH) signaling, are responsible for the development of malformation syndromes such as Greig-cephalopolysyndactyly-syndrome (GCPS), or Pallister-Hall-syndrome (PHS). Mutations that lead to loss of function of the protein and to haploinsufficiency cause GCPS, while truncating mutations that result in constitutive repressor function of GLI3 lead to PHS. As an exception, some point mutations in the C-terminal part of GLI3 observed in GCPS patients have so far not been linked to loss of function. We have shown recently that protein phosphatase 2A (PP2A) regulates the nuclear localization and transcriptional activity a of GLI3 function.

Principal Findings
We have shown recently that protein phosphatase 2A (PP2A) and the ubiquitin ligase MID1 regulate the nuclear localization and transcriptional activity of GLI3. Here we show mapping of the functional interaction between the MID1-α4-PP2A complex and GLI3 to a region between amino acid 568-1100 of GLI3. Furthermore we demonstrate that GCPS-associated point mutations, that are located in that region, lead to misregulation of the nuclear GLI3-localization and transcriptional activity. GLI3 phosphorylation itself however appears independent of its localization and remains untouched by either of the point mutations and by PP2A-activity, which suggests involvement of an as yet unknown GLI3 interaction partner, the phosphorylation status of which is regulated by PP2A activity, in the control of GLI3 subcellular localization and activity.

The present findings provide an explanation for the pathogenesis of GCPS in patients carrying C-terminal point mutations, and close the gap in our understanding of how GLI3-genotypes give rise to particular phenotypes. Furthermore, they provide a molecular explanation for the phenotypic overlap between Opitz syndrome patients with dysregulated PP2A-activity and syndromes caused by GLI3-mutations.
Comment of the Author/Creator:email: rainer.schneider@uibk.ac.at
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:Charité University Hospital, Department of Dermatology, Berlin, Germany
Institute of Biochemistry and Center for Molecular Biosciences Innsbruck (CMBI), Innsbruck, Austria
Center for Human Genetics, Phillipps University, Marburg, Germany
Ninewells Hospital, Department of Neuroscience and Pathology, Dundee, United Kingdom