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1.
Blood ; 112(12): 4723-8, 2008 Dec 01.
Article in English | MEDLINE | ID: mdl-18809758

ABSTRACT

Hepatic siderosis is common in patients with porphyria cutanea tarda (PCT). Mutations in the hereditary hemochromatosis (hh) gene (HFE) explain the siderosis in approximately 20% patients, suggesting that the remaining occurrences result from additional genetic and environmental factors. Two genes known to modify iron loading in hh are hepcidin (HAMP) and hemojuvelin (HJV). To determine if mutations in or expression of these genes influenced iron overload in PCT, we compared sequences of HAMP and HJV in 96 patients with PCT and 88 HFE C282Y homozygotes with marked hepatic iron overload. We also compared hepatic expression of these and other iron-related genes in a group of patients with PCT and hh. Two intronic polymorphisms in HJV were associated with elevated serum ferritin in HFE C282Y homozygotes. No exonic polymorphisms were identified. Sequencing of HAMP revealed exonic polymorphisms in 2 patients with PCT: heterozygosity for a G-->A transition (G71D substitution) in one and heterozygosity for an A-->G transition (K83R substitution) in the other. Hepatic HAMP expression in patients with PCT was significantly reduced, regardless of HFE genotype, when compared with patients with hh but without PCT with comparable iron overload. These data indicate that the hepatic siderosis associated with PCT likely results from dysregulated HAMP.


Subject(s)
Antimicrobial Cationic Peptides/genetics , Porphyria Cutanea Tarda/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , DNA Mutational Analysis , Down-Regulation/physiology , Female , Gene Expression Profiling , Hemochromatosis Protein , Hepcidins , Histocompatibility Antigens Class I/genetics , Humans , Infant , Liver Diseases/etiology , Liver Diseases/genetics , Male , Membrane Proteins/genetics , Middle Aged , Oligonucleotide Array Sequence Analysis , Porphyria Cutanea Tarda/complications , Siderosis/etiology , Siderosis/genetics , Young Adult
2.
J Virol ; 76(20): 10417-26, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12239318

ABSTRACT

To understand the regulation of cap-dependent translation initiation mediated by specific 5' untranslated region (UTR) RNA-protein interactions in mammalian cells, we have studied the selective translation of influenza virus mRNAs. Previous work has shown that the host cell mRNA binding protein guanine-rich sequence factor 1 (GRSF-1) bound specifically to conserved viral 5' UTR sequences and stimulated translation of viral 5' UTR-driven mRNAs in vitro. In the present study, we have characterized the functional domains of GRSF-1 and mapped the RNA binding activity of GRSF-1 to RRM 2 (amino acids 194 to 275) with amino-terminal deletion glutathione S-transferase (GST)-GRSF-1 proteins. When these mutants were assayed for functional activity in vitro, deletion of an Ala-rich region (Delta[2-94]) appeared to diminish translational stimulation, while deletion of the Ala-rich region in addition to RRM 1 (Delta[2-194]) resulted in a 4-fold increase in translational activation over wild-type GRSF-1 (an overall 20-fold increase in activity). We have also mapped the GRSF-1 RNA binding site on influenza virus NP and NS1 5' UTRs, which was determined to be the sequence AGGGU. With polysome fractionation and cDNA microarray analysis, we have identified cellular and viral mRNAs containing putative GRSF-1 binding sites that were transcriptionally up-regulated and selectively recruited to polyribosomes following influenza virus infection. Taken together, these studies demonstrate that RRM 2 is critical for GRSF-1 RNA binding and translational activity. Further, our data suggest GRSF-1 functions by selectively recruiting cellular and viral mRNAs containing 5' UTR GRSF-1 binding sites to polyribosomes, which is mediated through interactions with cellular proteins.


Subject(s)
5' Untranslated Regions/metabolism , Orthomyxoviridae/genetics , Poly(A)-Binding Proteins , Protein Biosynthesis , RNA, Viral/metabolism , RNA-Binding Proteins/metabolism , Base Sequence , Binding Sites , Eukaryotic Cells , HeLa Cells , Humans , Influenza A virus/genetics , Molecular Sequence Data , Nucleocapsid Proteins , Nucleoproteins/genetics , Polyribosomes/metabolism , RNA-Binding Proteins/genetics , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Viral Core Proteins/genetics , Viral Matrix Proteins/genetics , Viral Nonstructural Proteins/genetics , Viral Proteins/biosynthesis , Viral Proteins/genetics
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