title: Hereditary hemochromatosis: mutations in genes involved in iron homeostasis in Brazilian patients.
abstract: BACKGROUND
  p.C282Y mutation and rare variants in the HFE gene have been associated with hereditary hemochromatosis (HH). HH is also caused by mutations in other genes, such as the hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1). The low rate homozygous p.C282Y mutation in Brazil is suggestive that mutations in non-HFE genes may be linked to HH phenotype.
  
  
  OBJECTIVE
  To screen exon-by-exon DNA sequences of HFE, HJV, HAMP, TFR2 and SLC40A1 genes to characterize the molecular basis of HH in a sample of the Brazilian population.
  
  
  METHODS
  Fifty-one patients with primary iron overload (transferrin saturation ≥50% in females and ≥60% in males) were selected. Subsequent bidirectional DNA sequencing of HFE, HJV, HAMP, TFR2 and SLC40A1 exons was performed.
  
  
  RESULTS
  Thirty-seven (72.5%) out of the 51 patients presented at least one HFE mutation. The most frequent genotype associated with HH was the homozygous p.C282Y mutation (n=11, 21.6%). In addition, heterozygous HFE p.S65C mutation was found in combination with p.H63D in two patients and homozygous HFE p.H63D was found in two patients as well. Sequencing in the HJV and HAMP genes revealed HJV p.E302K, HJV p.A310G, HJV p.G320V and HAMP p.R59G alterations. Molecular and clinical diagnosis of juvenile hemochromatosis (homozygous form for the HJV p.G320V) was described for the first time in Brazil. Three TFR2 polymorphisms (p.A75V, p.A617A and p.R752H) and six SLC40A1 polymorphisms (rs13008848, rs11568351, rs11568345, rs11568344, rs2304704, rs11568346) and the novel mutation SLC40A1 p.G204S were also found.
  
  
  CONCLUSIONS
  The HFE p.C282Y in homozygosity or in heterozygosity with p.H63D was the most frequent mutation associated with HH in this sample. The HJV p.E302K and HAMP p.R59G variants, and the novel SLC40A1 p.G204S mutation may also be linked to primary iron overload but their role in the pathophysiology of HH remain to be elucidated.
authors.affiliation: Department of Clinical Chemistry and Toxicology, School of Pharmaceutical Sciences, University of Sao Paulo, SP, Brazil. pacaleb@usp.br
authors.forename: Paulo C J L
authors.initials: PC
authors.lastname: Santos
authors.forename: Rodolfo D
authors.initials: RD
authors.lastname: Cançado
authors.forename: Alexandre C
authors.initials: AC
authors.lastname: Pereira
authors.forename: Isolmar T
authors.initials: IT
authors.lastname: Schettert
authors.forename: Renata A G
authors.initials: RA
authors.lastname: Soares
authors.forename: Regina A
authors.initials: RA
authors.lastname: Pagliusi
authors.forename: Rosario D C
authors.initials: RD
authors.lastname: Hirata
authors.forename: Mario H
authors.initials: MH
authors.lastname: Hirata
authors.forename: Ana C
authors.initials: AC
authors.lastname: Teixeira
authors.forename: Maria Stella
authors.initials: MS
authors.lastname: Figueiredo
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Chiattone
authors.forename: Jose E
authors.initials: JE
authors.lastname: Krieger
authors.forename: Elvira M
authors.initials: EM
authors.lastname: Guerra-Shinohara
mesh_terms: D000293:Adolescent; D000328:Adult; D001938:Brazil / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006432:Hemochromatosis / Q000151:congenital* / Q000235:genetics; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007501:Iron