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Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal)

Iron overload is associated with acquired and genetic conditions, the most common being hereditary hemochromatosis (HH) type-I, caused by HFE mutations. Here, we conducted a hospital-based case-control study of 41 patients from the São Miguel Island (Azores, Portugal), six belonging to a family with...

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Autores principales: Branco, Claudia C., Gomes, Cidália T., De Fez, Laura, Bulhões, Sara, Brilhante, Maria José, Pereirinha, Tânia, Cabral, Rita, Rego, Ana Catarina, Fraga, Cristina, Miguel, António G., Brasil, Gracinda, Macedo, Paula, Mota-Vieira, Luisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621060/
https://www.ncbi.nlm.nih.gov/pubmed/26501199
http://dx.doi.org/10.1371/journal.pone.0140228
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author Branco, Claudia C.
Gomes, Cidália T.
De Fez, Laura
Bulhões, Sara
Brilhante, Maria José
Pereirinha, Tânia
Cabral, Rita
Rego, Ana Catarina
Fraga, Cristina
Miguel, António G.
Brasil, Gracinda
Macedo, Paula
Mota-Vieira, Luisa
author_facet Branco, Claudia C.
Gomes, Cidália T.
De Fez, Laura
Bulhões, Sara
Brilhante, Maria José
Pereirinha, Tânia
Cabral, Rita
Rego, Ana Catarina
Fraga, Cristina
Miguel, António G.
Brasil, Gracinda
Macedo, Paula
Mota-Vieira, Luisa
author_sort Branco, Claudia C.
collection PubMed
description Iron overload is associated with acquired and genetic conditions, the most common being hereditary hemochromatosis (HH) type-I, caused by HFE mutations. Here, we conducted a hospital-based case-control study of 41 patients from the São Miguel Island (Azores, Portugal), six belonging to a family with HH type-I pseudodominant inheritance, and 35 unrelated individuals fulfilling the biochemical criteria of iron overload compatible with HH type-I. For this purpose, we analyzed the most common HFE mutations– c.845G>A [p.Cys282Tyr], c.187C>G [p.His63Asp], and c.193A>T [p.Ser65Cys]. Results revealed that the family’s HH pseudodominant pattern is due to consanguineous marriage of HFE-c.845G>A carriers, and to marriage with a genetically unrelated spouse that is a -c.187G carrier. Regarding unrelated patients, six were homozygous for c.845A, and three were c.845A/c.187G compound heterozygous. We then performed sequencing of HFE exons 2, 4, 5 and their intron-flanking regions. No other mutations were observed, but we identified the -c.340+4C [IVS2+4C] splice variant in 26 (74.3%) patients. Functionally, the c.340+4C may generate alternative splicing by HFE exon 2 skipping and consequently, a protein missing the α1-domain essential for HFE/ transferrin receptor-1 interactions. Finally, we investigated HFE mutations configuration with iron overload by determining haplotypes and genotypic profiles. Results evidenced that carriers of HFE-c.187G allele also carry -c.340+4C, suggesting in-cis configuration. This data is corroborated by the association analysis where carriers of the complex allele HFE-c.[187C>G;340+4T>C] have an increased iron overload risk (RR = 2.08, 95% CI = 1.40−2.94, p<0.001). Therefore, homozygous for this complex allele are at risk of having iron overload because they will produce two altered proteins—the p.63Asp [c.187G], and the protein lacking 88 amino acids encoded by exon 2. In summary, we provide evidence that the complex allele HFE-c.[187C>G;340+4T>C] has a role, as genetic predisposition factor, on iron overload in the São Miguel population. Independent replication studies in other populations are needed to confirm this association.
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spelling pubmed-46210602015-10-29 Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal) Branco, Claudia C. Gomes, Cidália T. De Fez, Laura Bulhões, Sara Brilhante, Maria José Pereirinha, Tânia Cabral, Rita Rego, Ana Catarina Fraga, Cristina Miguel, António G. Brasil, Gracinda Macedo, Paula Mota-Vieira, Luisa PLoS One Research Article Iron overload is associated with acquired and genetic conditions, the most common being hereditary hemochromatosis (HH) type-I, caused by HFE mutations. Here, we conducted a hospital-based case-control study of 41 patients from the São Miguel Island (Azores, Portugal), six belonging to a family with HH type-I pseudodominant inheritance, and 35 unrelated individuals fulfilling the biochemical criteria of iron overload compatible with HH type-I. For this purpose, we analyzed the most common HFE mutations– c.845G>A [p.Cys282Tyr], c.187C>G [p.His63Asp], and c.193A>T [p.Ser65Cys]. Results revealed that the family’s HH pseudodominant pattern is due to consanguineous marriage of HFE-c.845G>A carriers, and to marriage with a genetically unrelated spouse that is a -c.187G carrier. Regarding unrelated patients, six were homozygous for c.845A, and three were c.845A/c.187G compound heterozygous. We then performed sequencing of HFE exons 2, 4, 5 and their intron-flanking regions. No other mutations were observed, but we identified the -c.340+4C [IVS2+4C] splice variant in 26 (74.3%) patients. Functionally, the c.340+4C may generate alternative splicing by HFE exon 2 skipping and consequently, a protein missing the α1-domain essential for HFE/ transferrin receptor-1 interactions. Finally, we investigated HFE mutations configuration with iron overload by determining haplotypes and genotypic profiles. Results evidenced that carriers of HFE-c.187G allele also carry -c.340+4C, suggesting in-cis configuration. This data is corroborated by the association analysis where carriers of the complex allele HFE-c.[187C>G;340+4T>C] have an increased iron overload risk (RR = 2.08, 95% CI = 1.40−2.94, p<0.001). Therefore, homozygous for this complex allele are at risk of having iron overload because they will produce two altered proteins—the p.63Asp [c.187G], and the protein lacking 88 amino acids encoded by exon 2. In summary, we provide evidence that the complex allele HFE-c.[187C>G;340+4T>C] has a role, as genetic predisposition factor, on iron overload in the São Miguel population. Independent replication studies in other populations are needed to confirm this association. Public Library of Science 2015-10-26 /pmc/articles/PMC4621060/ /pubmed/26501199 http://dx.doi.org/10.1371/journal.pone.0140228 Text en © 2015 Branco et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Branco, Claudia C.
Gomes, Cidália T.
De Fez, Laura
Bulhões, Sara
Brilhante, Maria José
Pereirinha, Tânia
Cabral, Rita
Rego, Ana Catarina
Fraga, Cristina
Miguel, António G.
Brasil, Gracinda
Macedo, Paula
Mota-Vieira, Luisa
Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal)
title Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal)
title_full Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal)
title_fullStr Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal)
title_full_unstemmed Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal)
title_short Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal)
title_sort carriers of the complex allele hfe c.[187c>g;340+4t>c] have increased risk of iron overload in são miguel island population (azores, portugal)
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621060/
https://www.ncbi.nlm.nih.gov/pubmed/26501199
http://dx.doi.org/10.1371/journal.pone.0140228
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