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Abnormal regulation of HFE mRNA expression does not contribute to primary iron overload.
Haematologica. 2000 Aug; 85(8):787-91.H

Abstract

BACKGROUND AND OBJECTIVES

Hereditary hemochromatosis (HHC) is a common, recessively inherited, genetic disorder associated with an abnormality of the HFE gene. Subjects homozygous for a point mutation in the gene coding sequence, leading to the amino acid substitution C282Y, are usually affected by the disease. A second point mutation, causing the amino acid substitution H63D, has been described, and compound heterozygotes for the two mutations or homozygotes for the H63D mutation are at risk of developing a milder form of HHC. In populations of northern European origin the C282Y substitution accounts for more than 90% of cases of HHC. In Italy, however, fewer than 70% of patients with HHC are homozygous or compound heterozygous for HFE mutations. Even in the absence of mutations in its coding region, the HFE gene might be involved in the pathogenesis of HHC through inhibition of transcription of the gene or reduced stability of its mRNA.

DESIGN AND METHODS

Since little is known about the regulation of HFE expression, we investigated 17 subjects heterozygous for one of the HFE mutations and with biochemical evidence of iron overload and compared the levels of wild type and mutated mRNAs in their peripheral blood cells. c-DNA regions flanking the mutated codons were amplified by reverse transcriptase polymerase chain reaction (PCR). PCR products derived from the two alleles were differentiated and quantified by digestion with restriction enzymes, electrophoresis in an agarose gel stained with ethidium bromide and densitometric scanning of the gel.

RESULTS

In all cases wild type and mutated mRNAs were expressed at similar levels, suggesting that reduced expression of an HFE allele coding a normal protein is not involved in the pathogenesis of iron overload. However, we can not rule out that a tissue specific regulation of HFE expression in the cells directly involved in iron absorption is altered and contributes to the pathogenesis of the disease. E INTERPRETATION AND CONCLUSIONS: Our results suggest that primary iron overload is a multigenic syndrome; this hypothesis is strongly supported by the recent demonstration that the juvenile hemochromatosis locus maps to human chromosome 1q.

Authors+Show Affiliations

Department of Internal Medicine and Medical Therapy, Section of Internal Medicine and Medical Oncology, University of Pavia Medical School and IRCCS Policlinico S. Matteo, Pavia, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10942923

Citation

Vercesi, E, et al. "Abnormal Regulation of HFE mRNA Expression Does Not Contribute to Primary Iron Overload." Haematologica, vol. 85, no. 8, 2000, pp. 787-91.
Vercesi E, Cerani P, Rolandi V, et al. Abnormal regulation of HFE mRNA expression does not contribute to primary iron overload. Haematologica. 2000;85(8):787-91.
Vercesi, E., Cerani, P., Rolandi, V., Rovati, A., & Bergamaschi, G. (2000). Abnormal regulation of HFE mRNA expression does not contribute to primary iron overload. Haematologica, 85(8), 787-91.
Vercesi E, et al. Abnormal Regulation of HFE mRNA Expression Does Not Contribute to Primary Iron Overload. Haematologica. 2000;85(8):787-91. PubMed PMID: 10942923.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Abnormal regulation of HFE mRNA expression does not contribute to primary iron overload. AU - Vercesi,E, AU - Cerani,P, AU - Rolandi,V, AU - Rovati,A, AU - Bergamaschi,G, PY - 2000/8/16/pubmed PY - 2001/2/28/medline PY - 2000/8/16/entrez SP - 787 EP - 91 JF - Haematologica JO - Haematologica VL - 85 IS - 8 N2 - BACKGROUND AND OBJECTIVES: Hereditary hemochromatosis (HHC) is a common, recessively inherited, genetic disorder associated with an abnormality of the HFE gene. Subjects homozygous for a point mutation in the gene coding sequence, leading to the amino acid substitution C282Y, are usually affected by the disease. A second point mutation, causing the amino acid substitution H63D, has been described, and compound heterozygotes for the two mutations or homozygotes for the H63D mutation are at risk of developing a milder form of HHC. In populations of northern European origin the C282Y substitution accounts for more than 90% of cases of HHC. In Italy, however, fewer than 70% of patients with HHC are homozygous or compound heterozygous for HFE mutations. Even in the absence of mutations in its coding region, the HFE gene might be involved in the pathogenesis of HHC through inhibition of transcription of the gene or reduced stability of its mRNA. DESIGN AND METHODS: Since little is known about the regulation of HFE expression, we investigated 17 subjects heterozygous for one of the HFE mutations and with biochemical evidence of iron overload and compared the levels of wild type and mutated mRNAs in their peripheral blood cells. c-DNA regions flanking the mutated codons were amplified by reverse transcriptase polymerase chain reaction (PCR). PCR products derived from the two alleles were differentiated and quantified by digestion with restriction enzymes, electrophoresis in an agarose gel stained with ethidium bromide and densitometric scanning of the gel. RESULTS: In all cases wild type and mutated mRNAs were expressed at similar levels, suggesting that reduced expression of an HFE allele coding a normal protein is not involved in the pathogenesis of iron overload. However, we can not rule out that a tissue specific regulation of HFE expression in the cells directly involved in iron absorption is altered and contributes to the pathogenesis of the disease. E INTERPRETATION AND CONCLUSIONS: Our results suggest that primary iron overload is a multigenic syndrome; this hypothesis is strongly supported by the recent demonstration that the juvenile hemochromatosis locus maps to human chromosome 1q. SN - 0390-6078 UR - https://www.unboundmedicine.com/medline/citation/10942923/Abnormal_regulation_of_HFE_mRNA_expression_does_not_contribute_to_primary_iron_overload_ L2 - http://www.diseaseinfosearch.org/result/3874 DB - PRIME DP - Unbound Medicine ER -