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Clinical Chemistry 49: 1981-1988, 2003. First published November 13, 2003; 10.1373/clinchem.2003.023440
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Right arrow Molecular Diagnostics and Genetics
(Clinical Chemistry. 2003;49:1981-1988.)
© 2003 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Identification of New Mutations of the HFE, Hepcidin, and Transferrin Receptor 2 Genes by Denaturing HPLC Analysis of Individuals with Biochemical Indications of Iron Overload

Giorgio Biasiottoa,1, Silvana Belloli1, Giuseppina Ruggeri1, Isabella Zanella1, Gianmario Gerardi1, Marcella Corrado1, Elena Gobbi1, Alberto Albertini1 and Paolo Arosio1

1 Dipartimento Materno Infantile e Tecnologie Biomediche, University of Brescia, viale Europa 11, 25123 Brescia, Italy.

aAuthor for correspondence. Fax 39-030-307-251; e-mail arosio{at}med.unibs.it.

Background: Hereditary hemochromatosis is a recessive disorder characterized by iron accumulation in parenchymal cells, followed by organ damage and failure. The disorder is mainly attributable to the C282Y and H63D mutations in the HFE gene, but additional mutations in the HFE, transferrin receptor 2 (TfR2), and hepcidin genes have been reported. The copresence of mutations in different genes may explain the phenotypic heterogeneity of the disorder and its variable penetrance.

Methods: We used denaturing HPLC (DHPLC) for rapid DNA scanning of the HFE (exons 2, 3, and 4), hepcidin, and TfR2 (exons 2, 4 and 6) genes in a cohort of 657 individuals with altered indicators of iron status.

Results: DHPLC identification of C282Y and H63D HFE alleles was in perfect agreement with the restriction endonuclease assay. Fourteen DNA samples were heterozygous for the HFE S65C mutation. In addition, we found novel mutations: two in HFE (R66C in exon 2 and R224G in exon 4), one in the hepcidin gene (G71D), and one in TfR2 (V22I), plus several intronic or silent substitutions. Six of the seven individuals with hepcidin or TfR2 coding mutations carried also HFE C282Y or S65C mutations.

Conclusion: DHPLC is an efficient method for mutational screening for the genes involved in hereditary hemochromatosis and for the study of their copresence.




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