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) 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.
Unidad de Ferropatología, Departamento de Medicina Interna, Instituto de Investigación Sanitaria del Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Alejandro
A
Del-Castillo-Rueda
María-Isabel
MI
Moreno-Carralero
Nuria
N
Cuadrado-Grande
Luis-Antonio
LA
Alvarez-Sala-Walther
Rafael
R
Enríquez-de-Salamanca
Manuel
M
Méndez
María-Josefa
MJ
Morán-Jiménez
D000328:Adult; D027682:Cation Transport Proteins / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D005838:Genotype; D006432:Hemochromatosis / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D019190:Iron Overload / Q000175:diagnosis / Q000209:etiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011990:Receptors, Transferrin / Q000235:genetics*; D000098742:Ferroportin
D027682:Cation Transport Proteins; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin; C503640:TFR2 protein, human; D000098742:Ferroportin; D004247:DNA