Evidence for Haploinsufficiency of the Human HNF1α Gene Revealed by Functional Characterization of MODY3-Associated Mutations
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H. Thomas
Abstract
Hepatocyte nuclear factor (HNF)1α is a homeodomaincontaining transcription factor participating in the regulation of gene expression in liver, kidney, gut and pancreas of vertebrates. In humans mutations in the HNF1α gene are responsible for one form of maturity onset diabetes of the young (MODY3). To define the molecular mechanism underlying MODY3 we investigated the functional properties of seven MODY3- associated mutations representing the spectrum of different kinds of mutations affecting all functional domains of the protein. The mutations introduced into an expression vector encoding human HNF1α include inframe deletion (ΔN127), nonsense (Q7X, R171X), frameshift (P291fsinsC) and missense (R229Q, P447L, T620I) mutations. Gel retardation and reporter gene assays showed that the functional properties of these mutants differ dramatically, but none of these mutants act in a dominant negative manner. Moreover, the mRNA stability of the mutants ΔN127, R171X, P291fsinsC and T547E548fsdelTG is impaired compared to the wildtype sequence in transfected cells. This decreased RNA stability is independent of the presence of an intron in the expression vector and thus differs from mechanisms known to be involved in nonsensemediated decay (NMD). Our results suggest that haploinsufficiency of HNF1α is responsible for the pathogenesis of MODY3.
Copyright © 2002 by Walter de Gruyter GmbH & Co. KG
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Articles in the same Issue
- Pigment Epithelium-Derived Factor (PEDF), a Serpin with Potent Anti-Angiogenic and Neurite Outgrowth-promoting Properties
- Mechanism of Inhibition of RNA Polymerase I Transcription by DNA-dependent Protein Kinase
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- Effects of Antineoplastic Agents on Cytoplasmic and Membrane-Bound Heat Shock Protein 70 (Hsp70) Levels
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- Substrate Specificity and Inhibitor Studies of a Membrane-Bound Ganglioside Sialidase Isolated from Human Brain Tissue
- Specificity Determinants in the Interaction of Apolipoprotein(a) Kringles with Tetranectin and LDL
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- Molecular Cloning and Chimerisation of an Inhibitory Anti-Cathepsin B Antibody and Its Expression in Chinese Hamster Ovary Cells
- Application of Peptides Containing the Cleavage Sequence of Pro-TNFα in Assessing TACE Activity of Whole Cells
