Human Molecular Genetics Advance Access published online on October 27, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh338
© 2004 by Oxford University Press
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1 Biologie du Développement, UMR 7622 - CNRS - Université Pierre et Marie Curie, 9 quai St Bernard, 75005 Paris, France
* To whom correspondence should be addressed. Mutations in the HNF1
Article
HNF1
/TCF2 mutations impair transactivation potential through altered co-regulator recruitment
2 Institute of Molecular Biology and Biotechnology, FORTH 1527, Vassilika Vouton, 711 10 Herakleion, Crete, Greece
3 Hôpital Robert-Debré- Service de Néphrologie, 48, bd Serrurier, 75019 Paris, France chantal.loirat@rdb.ap-hop-paris.fr
4 Hôpital de Tours. Centre Hospitalier Universitaire, 49 bd Beranger, 37044 Tours cedex. France
5 Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75012 Paris. France
6 Biologie du Développement, UMR 7622 - CNRS - Université Pierre et Marie Curie, 9 quai St Bernard, Bâtiment C, case 24, 75005 Paris Cedex 05, France
Silvia Cereghini, E-mail: Silvia.Cereghini{at}snv.jussieu.fr
Abstract 
gene, encoding the dimeric POU-homeodomain transcription factor HNF1(TCF2 or vHNF1), cause various phenotypes including Maturity Onset Diabetes of the Young 5, and abnormalities in kidney, pancreas and genital tract development. To gain insight into the molecular mechanisms underlying these phenotypes and into the structure of HNF1, we functionally characterised eight disease-causing mutations predicted to produce protein truncations, amino acids substitutions or frameshift deletions in different domains of the protein. Truncated mutations, retaining the dimerisation domain, displayed defective nuclear localisation and weak dominant-negative activity when co-expressed with the wild-type protein. A frameshift mutation located within the C-terminal QSP-rich domain partially reduced transcriptional activity, whereas selective deletion of this domain abolished transactivation. All five missense mutations, which concern POU-specific and homeodomain residues, were correctly expressed and localised to the nucleus. Although having different effects on DNA-binding capacity, which ranged from complete loss to a mild reduction, these mutations exhibited a severe reduction in their transactivation capacity. The transcriptional impairment of those mutants, whose DNA-binding activity was weakly or not affected, correlated with the loss of association with one of the histone-acetyltransferases CBP or PCAF. In contrast to wild-type HNF1, whose transactivation potential depends on the synergistic action of CBP and PCAF, the activity of these mutants was not increased by the synergistic action of these two coactivators or by treatment with the specific histone-deacetylase inhibitor TSA. Our findings suggest that the complex syndrome associated with HNF1-MODY5 mutations arise from defective DNA-binding or transactivation function through impaired coactivator recruitment.
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