Mutations in the HFE, TFR2, and SLC40A1 genes in patients with hemochromatosis

Hereditary hemochromatosis causes iron overload and is associated with a variety of genetic and phenotypic conditions. Early diagnosis is important so that effective treatment can be administered and the risk of tissue damage avoided. Most patients are homozygous for the c.845G>A (p.C282Y) mutati...

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Veröffentlicht in:Gene 2012-10, Vol.508 (1), p.15-20
Hauptverfasser: del-Castillo-Rueda, Alejandro, Moreno-Carralero, María-Isabel, Cuadrado-Grande, Nuria, Álvarez-Sala-Walther, Luis-Antonio, Enríquez-de-Salamanca, Rafael, Méndez, Manuel, Morán-Jiménez, María-Josefa
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container_start_page 15
container_title Gene
container_volume 508
creator del-Castillo-Rueda, Alejandro
Moreno-Carralero, María-Isabel
Cuadrado-Grande, Nuria
Álvarez-Sala-Walther, Luis-Antonio
Enríquez-de-Salamanca, Rafael
Méndez, Manuel
Morán-Jiménez, María-Josefa
description Hereditary hemochromatosis causes iron overload and is associated with a variety of genetic and phenotypic conditions. Early diagnosis is important so that effective treatment can be administered and the risk of tissue damage avoided. Most patients are homozygous for the c.845G>A (p.C282Y) mutation in the HFE gene; however, rare forms of genetic iron overload must be diagnosed using a specific genetic analysis. We studied the genotype of 5 patients who had hyperferritinemia and an iron overload phenotype, but not classic mutations in the HFE gene. Two patients were undergoing phlebotomy and had no iron overload, 1 with metabolic syndrome and no phlebotomy had mild iron overload, and 2 patients had severe iron overload despite phlebotomy. The patients' first-degree relatives also underwent the analysis. We found 5 not previously published mutations: c.-408_-406delCAA in HFE, c.1118G>A (p.G373D), c.1473G>A (p.E491E) and c.2085G>C (p.S695S) in TFR2; and c.-428_-427GG>TT in SLC40A1. Moreover, we found 3 previously published mutations: c.221C>T (p.R71X) in HFE; c.1127C>A (p.A376D) in TFR2; and c.539T>C (p.I180T) in SLC40A1. Four patients were double heterozygous or compound heterozygous for the mutations mentioned above, and the patient with metabolic syndrome was heterozygous for a mutation in the TFR2 gene. Our findings show that hereditary hemochromatosis is clinically and genetically heterogeneous and that acquired factors may modify or determine the phenotype. ► Hereditary hemochromatosis is clinically and genetically heterogeneous. ► Genetic analysis is challenged when mutation C2812Y in HFE is absent. ► We found published and unpublished mutations in HFE, TFR2 and SLC40A1 genes.
doi_str_mv 10.1016/j.gene.2012.07.069
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Early diagnosis is important so that effective treatment can be administered and the risk of tissue damage avoided. Most patients are homozygous for the c.845G&gt;A (p.C282Y) mutation in the HFE gene; however, rare forms of genetic iron overload must be diagnosed using a specific genetic analysis. We studied the genotype of 5 patients who had hyperferritinemia and an iron overload phenotype, but not classic mutations in the HFE gene. Two patients were undergoing phlebotomy and had no iron overload, 1 with metabolic syndrome and no phlebotomy had mild iron overload, and 2 patients had severe iron overload despite phlebotomy. The patients' first-degree relatives also underwent the analysis. We found 5 not previously published mutations: c.-408_-406delCAA in HFE, c.1118G&gt;A (p.G373D), c.1473G&gt;A (p.E491E) and c.2085G&gt;C (p.S695S) in TFR2; and c.-428_-427GG&gt;TT in SLC40A1. Moreover, we found 3 previously published mutations: c.221C&gt;T (p.R71X) in HFE; c.1127C&gt;A (p.A376D) in TFR2; and c.539T&gt;C (p.I180T) in SLC40A1. Four patients were double heterozygous or compound heterozygous for the mutations mentioned above, and the patient with metabolic syndrome was heterozygous for a mutation in the TFR2 gene. Our findings show that hereditary hemochromatosis is clinically and genetically heterogeneous and that acquired factors may modify or determine the phenotype. ► Hereditary hemochromatosis is clinically and genetically heterogeneous. ► Genetic analysis is challenged when mutation C2812Y in HFE is absent. ► We found published and unpublished mutations in HFE, TFR2 and SLC40A1 genes.</description><identifier>ISSN: 0378-1119</identifier><identifier>EISSN: 1879-0038</identifier><identifier>DOI: 10.1016/j.gene.2012.07.069</identifier><identifier>PMID: 22890139</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Adult ; Cation Transport Proteins - genetics ; DNA - genetics ; Dysmetabolic iron overload syndrome (DIOS) ; early diagnosis ; Female ; Ferroportin (SLC40A1) ; genes ; genetic techniques and protocols ; Genotype ; hemochromatosis ; Hemochromatosis - complications ; Hemochromatosis - diagnosis ; Hemochromatosis - genetics ; Hemochromatosis Protein ; Hereditary hemochromatosis ; heterozygosity ; Heterozygote ; HFE ; Histocompatibility Antigens Class I - genetics ; homozygosity ; Homozygote ; Humans ; Hyperferritinemia ; Iron Overload - diagnosis ; Iron Overload - etiology ; Male ; Membrane Proteins - genetics ; metabolic syndrome ; Middle Aged ; mutation ; Mutation - genetics ; patients ; Phenotype ; Polymerase Chain Reaction ; Receptors, Transferrin - genetics ; risk ; Transferrin receptor 2 (TFR2)</subject><ispartof>Gene, 2012-10, Vol.508 (1), p.15-20</ispartof><rights>2012</rights><rights>Copyright © 2012. 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Early diagnosis is important so that effective treatment can be administered and the risk of tissue damage avoided. Most patients are homozygous for the c.845G&gt;A (p.C282Y) mutation in the HFE gene; however, rare forms of genetic iron overload must be diagnosed using a specific genetic analysis. We studied the genotype of 5 patients who had hyperferritinemia and an iron overload phenotype, but not classic mutations in the HFE gene. Two patients were undergoing phlebotomy and had no iron overload, 1 with metabolic syndrome and no phlebotomy had mild iron overload, and 2 patients had severe iron overload despite phlebotomy. The patients' first-degree relatives also underwent the analysis. We found 5 not previously published mutations: c.-408_-406delCAA in HFE, c.1118G&gt;A (p.G373D), c.1473G&gt;A (p.E491E) and c.2085G&gt;C (p.S695S) in TFR2; and c.-428_-427GG&gt;TT in SLC40A1. 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Our findings show that hereditary hemochromatosis is clinically and genetically heterogeneous and that acquired factors may modify or determine the phenotype. ► Hereditary hemochromatosis is clinically and genetically heterogeneous. ► Genetic analysis is challenged when mutation C2812Y in HFE is absent. ► We found published and unpublished mutations in HFE, TFR2 and SLC40A1 genes.</description><subject>Adult</subject><subject>Cation Transport Proteins - genetics</subject><subject>DNA - genetics</subject><subject>Dysmetabolic iron overload syndrome (DIOS)</subject><subject>early diagnosis</subject><subject>Female</subject><subject>Ferroportin (SLC40A1)</subject><subject>genes</subject><subject>genetic techniques and protocols</subject><subject>Genotype</subject><subject>hemochromatosis</subject><subject>Hemochromatosis - complications</subject><subject>Hemochromatosis - diagnosis</subject><subject>Hemochromatosis - genetics</subject><subject>Hemochromatosis Protein</subject><subject>Hereditary hemochromatosis</subject><subject>heterozygosity</subject><subject>Heterozygote</subject><subject>HFE</subject><subject>Histocompatibility Antigens Class I - genetics</subject><subject>homozygosity</subject><subject>Homozygote</subject><subject>Humans</subject><subject>Hyperferritinemia</subject><subject>Iron Overload - diagnosis</subject><subject>Iron Overload - etiology</subject><subject>Male</subject><subject>Membrane Proteins - genetics</subject><subject>metabolic syndrome</subject><subject>Middle Aged</subject><subject>mutation</subject><subject>Mutation - genetics</subject><subject>patients</subject><subject>Phenotype</subject><subject>Polymerase Chain Reaction</subject><subject>Receptors, Transferrin - genetics</subject><subject>risk</subject><subject>Transferrin receptor 2 (TFR2)</subject><issn>0378-1119</issn><issn>1879-0038</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1P3DAQhq0KVBbaP9AD9ZEDSf0RJ7bEZbViS6WFSgXOluNMWK828db2UvXf43ShR-Yyl2femXkQ-kJJSQmtv23KJxihZISykjQlqdUHNKOyUQUhXB6hGeGNLCil6gSdxrghuYRgH9EJY1IRytUM3d3uk0nOjxG7Eac14Jvl9SV-WP5il9iMHb5fLSoyp3ha9Y_ZZRzGFPEfl9Z4DYO36-AHk3x08RM67s02wufXfoYel9cPi5ti9fP7j8V8VVguSSq6vlYCqGBtJ5iVtaiJaNuG9yafTI2ilahpC03LQXRVVStJgYCtWsqktLbhZ-jikLsL_vceYtKDixa2WzOC30dNp9el4KrOKDugNvgYA_R6F9xgwt8M6cmj3ujpOT151KTR2WMeOn_N37cDdP9H3sRl4OsB6I3X5im4qB_vc4LIjiveiCoTVwcCsodnB0FHm8VZ6FwAm3Tn3XsXvADjwYok</recordid><startdate>20121015</startdate><enddate>20121015</enddate><creator>del-Castillo-Rueda, Alejandro</creator><creator>Moreno-Carralero, María-Isabel</creator><creator>Cuadrado-Grande, Nuria</creator><creator>Álvarez-Sala-Walther, Luis-Antonio</creator><creator>Enríquez-de-Salamanca, Rafael</creator><creator>Méndez, Manuel</creator><creator>Morán-Jiménez, María-Josefa</creator><general>Elsevier B.V</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20121015</creationdate><title>Mutations in the HFE, TFR2, and SLC40A1 genes in patients with hemochromatosis</title><author>del-Castillo-Rueda, Alejandro ; Moreno-Carralero, María-Isabel ; Cuadrado-Grande, Nuria ; Álvarez-Sala-Walther, Luis-Antonio ; Enríquez-de-Salamanca, Rafael ; Méndez, Manuel ; Morán-Jiménez, María-Josefa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c380t-df695e152bd52c865605bb73fa0371a914561be7b3e5d446981e0ec4b1288cc73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adult</topic><topic>Cation Transport Proteins - genetics</topic><topic>DNA - genetics</topic><topic>Dysmetabolic iron overload syndrome (DIOS)</topic><topic>early diagnosis</topic><topic>Female</topic><topic>Ferroportin (SLC40A1)</topic><topic>genes</topic><topic>genetic techniques and protocols</topic><topic>Genotype</topic><topic>hemochromatosis</topic><topic>Hemochromatosis - complications</topic><topic>Hemochromatosis - diagnosis</topic><topic>Hemochromatosis - genetics</topic><topic>Hemochromatosis Protein</topic><topic>Hereditary hemochromatosis</topic><topic>heterozygosity</topic><topic>Heterozygote</topic><topic>HFE</topic><topic>Histocompatibility Antigens Class I - genetics</topic><topic>homozygosity</topic><topic>Homozygote</topic><topic>Humans</topic><topic>Hyperferritinemia</topic><topic>Iron Overload - diagnosis</topic><topic>Iron Overload - etiology</topic><topic>Male</topic><topic>Membrane Proteins - genetics</topic><topic>metabolic syndrome</topic><topic>Middle Aged</topic><topic>mutation</topic><topic>Mutation - genetics</topic><topic>patients</topic><topic>Phenotype</topic><topic>Polymerase Chain Reaction</topic><topic>Receptors, Transferrin - genetics</topic><topic>risk</topic><topic>Transferrin receptor 2 (TFR2)</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>del-Castillo-Rueda, Alejandro</creatorcontrib><creatorcontrib>Moreno-Carralero, María-Isabel</creatorcontrib><creatorcontrib>Cuadrado-Grande, Nuria</creatorcontrib><creatorcontrib>Álvarez-Sala-Walther, Luis-Antonio</creatorcontrib><creatorcontrib>Enríquez-de-Salamanca, Rafael</creatorcontrib><creatorcontrib>Méndez, Manuel</creatorcontrib><creatorcontrib>Morán-Jiménez, María-Josefa</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Gene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>del-Castillo-Rueda, Alejandro</au><au>Moreno-Carralero, María-Isabel</au><au>Cuadrado-Grande, Nuria</au><au>Álvarez-Sala-Walther, Luis-Antonio</au><au>Enríquez-de-Salamanca, Rafael</au><au>Méndez, Manuel</au><au>Morán-Jiménez, María-Josefa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mutations in the HFE, TFR2, and SLC40A1 genes in patients with hemochromatosis</atitle><jtitle>Gene</jtitle><addtitle>Gene</addtitle><date>2012-10-15</date><risdate>2012</risdate><volume>508</volume><issue>1</issue><spage>15</spage><epage>20</epage><pages>15-20</pages><issn>0378-1119</issn><eissn>1879-0038</eissn><abstract>Hereditary hemochromatosis causes iron overload and is associated with a variety of genetic and phenotypic conditions. Early diagnosis is important so that effective treatment can be administered and the risk of tissue damage avoided. Most patients are homozygous for the c.845G&gt;A (p.C282Y) mutation in the HFE gene; however, rare forms of genetic iron overload must be diagnosed using a specific genetic analysis. We studied the genotype of 5 patients who had hyperferritinemia and an iron overload phenotype, but not classic mutations in the HFE gene. Two patients were undergoing phlebotomy and had no iron overload, 1 with metabolic syndrome and no phlebotomy had mild iron overload, and 2 patients had severe iron overload despite phlebotomy. The patients' first-degree relatives also underwent the analysis. We found 5 not previously published mutations: c.-408_-406delCAA in HFE, c.1118G&gt;A (p.G373D), c.1473G&gt;A (p.E491E) and c.2085G&gt;C (p.S695S) in TFR2; and c.-428_-427GG&gt;TT in SLC40A1. Moreover, we found 3 previously published mutations: c.221C&gt;T (p.R71X) in HFE; c.1127C&gt;A (p.A376D) in TFR2; and c.539T&gt;C (p.I180T) in SLC40A1. Four patients were double heterozygous or compound heterozygous for the mutations mentioned above, and the patient with metabolic syndrome was heterozygous for a mutation in the TFR2 gene. Our findings show that hereditary hemochromatosis is clinically and genetically heterogeneous and that acquired factors may modify or determine the phenotype. ► Hereditary hemochromatosis is clinically and genetically heterogeneous. ► Genetic analysis is challenged when mutation C2812Y in HFE is absent. ► We found published and unpublished mutations in HFE, TFR2 and SLC40A1 genes.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>22890139</pmid><doi>10.1016/j.gene.2012.07.069</doi><tpages>6</tpages></addata></record>
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identifier ISSN: 0378-1119
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subjects Adult
Cation Transport Proteins - genetics
DNA - genetics
Dysmetabolic iron overload syndrome (DIOS)
early diagnosis
Female
Ferroportin (SLC40A1)
genes
genetic techniques and protocols
Genotype
hemochromatosis
Hemochromatosis - complications
Hemochromatosis - diagnosis
Hemochromatosis - genetics
Hemochromatosis Protein
Hereditary hemochromatosis
heterozygosity
Heterozygote
HFE
Histocompatibility Antigens Class I - genetics
homozygosity
Homozygote
Humans
Hyperferritinemia
Iron Overload - diagnosis
Iron Overload - etiology
Male
Membrane Proteins - genetics
metabolic syndrome
Middle Aged
mutation
Mutation - genetics
patients
Phenotype
Polymerase Chain Reaction
Receptors, Transferrin - genetics
risk
Transferrin receptor 2 (TFR2)
title Mutations in the HFE, TFR2, and SLC40A1 genes in patients with hemochromatosis
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