HFE gene polymorphism defined by sequence‐based typing of the Brazilian population and a standardized nomenclature for HFE allele sequences

Abstract

The HFE molecule controls iron uptake from gut, and defects in the molecule have been associated with iron overload, particularly in hereditary hemochromatosis. The HFE gene including both coding and boundary intronic regions were sequenced in 304 Brazilian individuals, encompassing healthy individuals and patients exhibiting hereditary or acquired iron overload. Six sites of variation were detected: (1) H63D C>G in exon 2, (2) IVS2 (+4) T>C in intron 2, (3) a C>G transversion in intron 3, (4) C282Y G>A in exon 4, (5) IVS4 (-44) T>C in intron 4, and (6) a new guanine deletion (G>del) in intron 5, which were used for haplotype inference. Nine HFE alleles were detected and six of these were officially named on the basis of the HLA Nomenclature, defined by the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System, and published via the IPD-IMGT/HLA website. Four alleles, HFE*001, *002, *003, and *004 exhibited variation within their exon sequences.

Comprehensive analysis ofHFEgene in hereditary hemochromatosis and in diseases associated with acquired iron overload

“…The results regarding HFE alleles are presented in two forms: (1) as previously reported in the literature, including the single nucleotide polymorphism (SNP) reference number (rs), the usual SNP names (H63DC>G, C282YG>A, IVS2(+4)T>C and IVS4(-44)T>C) and new variation sites (Table 1); and (2) as the newly described official HFE allele nomenclature (Table 2)[10]. The location of the previously reported variation sites with respect to the nucleotide sequence that defined the new HFE nomenclature is illustrated in Figure 1.…”

“…The reconstruction of the meiotic phase generated nine alleles, included into four major allele groups ( HFE *001 to *004), as standardized by IMGT[10]. These allele groups encoded four distinct proteins (HFE*001 to *004) on the basis of polymorphic sites along the coding region, encompassing the H63DC>G (exon 2), IVS2(+4)T>C (intron 2), rs807209 (G>C intron 3), C282YG>A (exon 4) IVS4(-44)T>C (intron 4) and the new mutation (G>DEL at intron 5) (Table 2).…”

“…HFE nucleotide variations were retrieved from the NCBI (NC_000006.12) and Ensembl (ENSG00000010704) databases. Primer sequences, amplification conditions and allele nomenclature were defined as previously reported[10]. Sequencing was performed using an ABI 3500 sequencer (Applied Biosystems, Foster City, CA).…”

“…Structure of the HFE gene (ID# ENSG00000010704 - http://www.ensembl.org) at chromosome region 6p21.3, showing the reference number (rs) of variation sites (NCBI Data base - http://www.ncbi.nlm.nih.gov/snp), previously associated with iron disorders. Shaded grey areas indicate the sequenced gene regions and the respective pairs of primers, as previously described[10]. The combination of these variation sites, translated into the official nomenclature for HFE alleles is also shown in the bottom chart; i.e ., the combination of the triplet bases and respective encoded residues of the two most important mutations (H63DC>G and C282YG>A) that defined the four major HFE allele groups (mutated bases are shown in bold type).…”

HFE Gene Mutations as Predisposing Factors for Childhood Acute Lymphoblastic Leukaemia in Iraqi Patients

“…The 5' piece of exon 6 possesses a local stop codon and is accountable in encoding of the cytoplasmic tail. Hence, the whole-length of gene means only 6 exons [19]. The HFE protein holds 343 amino acids and possesses a peptide, a transmembrane region, binding region of an extracellular transferrin receptors (α1 and α2), a transmembrane segment, a short cytoplasmic tail, and an immunoglobulin-like α3 region [20] (Fig.…”