A Very Rare Association of Three Mutations of the<i>HFE</i>Gene for Hemochromatosis

Menardi, Giuseppe; Perotti, L.; Prucca, Maristella; Martini, S.; Prandi, Giancarlo; Peano, Gianmichele

doi:10.1089/10906570260471895

Cited by 10 publications

(7 citation statements)

References 18 publications

(22 reference statements)

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“…Among white participants with S65C, iron phenotypes and HFE genotypes were consistent with other reports [25][26][27]. One white had HFE H63D/E168Q, although it remains unclear that HFE E168Q causes a hemochromatosis phenotype, even in trans with other HFE missense mutations [27,28]. Two Asian men in the present study had high TS/SF and HFE V295E heterozygosity; one also had HFE H63D heterozygosity.…”

Section: Discussionsupporting

confidence: 91%

HFE, SLC40A1, HAMP, HJV, TFR2, and FTL mutations detected by denaturing high‐performance liquid chromatography after iron phenotyping and HFE C282Y and H63D genotyping in 785 HEIRS Study participants

Barton¹,

LaFreniere²,

Leiendecker–Foster³

et al. 2009

American J Hematol

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We sought to identify mutations that could explain iron phenotype heterogeneity in adults with previous HFE genotyping to detect C282Y and H63D. HEIRS Study participants genotyped for C282Y and H63D were designated as high transferrin saturation (TS) and/or serum ferritin (SF) (high TS/SF), low TS/SF, or controls. We grouped 191 C282Y homozygotes as high TS/SF, low TS/SF, or controls, and 594 other participants by race/ethnicity as high TS/SF or controls. Using denaturing high-performance liquid chromatography (DHPLC), we screened 20 regions of HFE, SLC40A1, HAMP, HJV, TFR2, and FTL in each participant. DHPLC analyses were successful in 99.3% of 791 participants and detected 117 different mutations. In C282Y homozygotes, 4.0% of high TS/SF participants had SLC40A1 Q248H, HAMP -72C>T, or HAMP R59G heterozygosity (0% Controls; P 5 0.1200). In whites, 4.1% with high TS/SF and 1.3% of controls had HFE S65C or E168Q (P 5 0.3049). HJV c.-6C>G and FTL L55L frequencies were greater in whites with high TS/SF than controls (0.0811 vs. 0.0200, P 5 0.0144; 0.5743 vs. 0.4400, P 5 0.0204, respectively). One Hispanic with high TS/SF (1.3%) had HAMP G71D heterozygosity. In blacks, SLC40A1 Q248H frequencies did not differ significantly between high TS/SF and control participants. Among Asians, 2.8% with high TS/SF were HFE V295A heterozygotes. Mutations other than HFE C282Y and H63D reported to be pathogenic were infrequently detected in high TS/SF participants. Genetic regions in linkage disequilibrium with HJV c.-6C>G and FTL L55L could partly explain high TS/SF phenotypes in whites. Am.

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Section: Discussionsupporting

confidence: 91%

HFE, SLC40A1, HAMP, HJV, TFR2, and FTL mutations detected by denaturing high‐performance liquid chromatography after iron phenotyping and HFE C282Y and H63D genotyping in 785 HEIRS Study participants

Barton¹,

LaFreniere²,

Leiendecker–Foster³

et al. 2009

American J Hematol

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“…1) highlights the potential significance of the mutation at codon 168, which was originally identified in South Africa (4). Mutation E168Q has also been recently detected in several subjects from Southern Europe and occurs in cis with mutation H63D (15, 16), which suggests that this chromosome was probably introduced into South Africa by settlers that came to this county many years ago. As in the case of mutations H63D and S65C (3, 17), other mutations with a possible mild phenotypic effect occurring in combination with mutation C282Y may at least in part explain clinical expression suggestive of iron overload.…”

Section: Resultsmentioning

confidence: 94%

Molecular diagnosis of hereditary hemochromatosis: application of a newly‐developed reverse‐hybridization assay in the South African population

Kotze¹,

Villiers²,

et al. 2004

Clinical Genetics

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A recently developed strip-assay for hemochromatosis provides a rapid method for simultaneous detection of multiple mutations, which among others includes the HFE gene mutations V53M, V59M, H63D, H63H, S65C, Q127H, E168Q, and C282Y, previously detected in the general South African population using gel-based mutation-screening methods. The objective of the study was to determine the frequency of the relatively rare mutations in samples selected for altered iron parameters or a family history of hereditary hemochromatosis (HH) as part of the validation process of the assay for routine diagnostic purposes. The study population consisted of 451 individuals previously screened for mutations C282Y and H63D by restriction enzyme analysis in order to confirm or possibly exclude a diagnosis of HH. These individuals were subjected to mutation screening using the commercially available hemochromatosis strip-assay. Previous positive results for mutations C282Y and H63D in 233 individuals confirmed the accuracy of the reverse-hybridization assay. Mutation S65C was detected in 13 Caucasians, including three compound heterozygotes. These constituted 2% (13/600) of the chromosomes without mutations C282Y or H63D. The African-specific HFE mutation V53M was detected in one out of 11 (9%) African subjects screened. Mutation E168Q was detected in a single Caucasian individual together with mutation H63D. Our data demonstrate the value of the strip-based technology in providing a rapid and reliable comprehensive test for simultaneous analysis of multiple mutations.

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“…Few cases have been reported showing that both the p.His63Asp and p.Cys282Tyr mutations are not mutually exclusive (Menardi et al, 2002). Complex alleles have been reported in several autosomal recessive diseases, often enhancing the pathogenic effect of each mutation alone.…”

Section: Discussionmentioning

confidence: 99%

“…The association of the p.Gly43Asp mutation in cis-combination with the p.His63Asp mutation (complex allele) co-inherited with the p.Cys282Tyr allele, is responsible for a classical form of HH in the proband. Few cases have been reported showing that both the p.His63Asp and p.Cys282Tyr mutations are not mutually exclusive (Menardi et al, 2002). Complex alleles have been reported in several autosomal recessive diseases, often enhancing the pathogenic effect of each mutation alone.…”

Section: Discussionmentioning

confidence: 99%

An unusual case of hemochromatosis due to a new compound heterozygosity in HFE (p.[Gly43Asp;His63Asp]+[Cys282Tyr]): structural implications with respect to binding with transferrin receptor 1

et al. 2007

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Most adults affected with HFE hereditary hemochromatosis (HH type 1, MIMmusical sharp 235200) are homozygous for the p.Cys282Tyr mutation in HFE (NC_000006.10, region 26195427 to 26205038). The aim of this study was to investigate the molecular basis of iron overload in a patient presenting with severe clinical HH with one c.845G>A (p.Cys282Tyr) allele only. Molecular and pedigree studies demonstrated the presence of the c.845G>A (p.Cys282Tyr) mutation in one allele whereas the other carried the c.187C>G (p.His63Asp) mutation plus a new c.128G>A (p.Gly43Asp) substitution in cis. A molecular modeling study of the p.[Gly43Asp;His63Asp] and p.His63Asp variants versus the wild type was carried out using molecular dynamics (MD) simulation in presence of implicit solvent. We found that the c.187C>G (p.His63Asp) mutation does not introduce any major change in the 1- domains of HFE whereas the c.128G>A (p.Gly43Asp) substitution is responsible for a modification of the dynamics and the structure of the Gln40-Ser45 loop, a critical region for HFE-TfR1 interaction thus impairing HFE-TfR1 normal contact. We conclude that the occurrence of complex alleles may be an alternative explanation for the variability of the phenotype in individuals who are compound heterozygous for c.[187C>G]+[845G>A] (p.[His63Asp]+[Cys282Tyr]).

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A Very Rare Association of Three Mutations of theHFEGene for Hemochromatosis

Cited by 10 publications

References 18 publications

HFE, SLC40A1, HAMP, HJV, TFR2, and FTL mutations detected by denaturing high‐performance liquid chromatography after iron phenotyping and HFE C282Y and H63D genotyping in 785 HEIRS Study participants

HFE, SLC40A1, HAMP, HJV, TFR2, and FTL mutations detected by denaturing high‐performance liquid chromatography after iron phenotyping and HFE C282Y and H63D genotyping in 785 HEIRS Study participants

Molecular diagnosis of hereditary hemochromatosis: application of a newly‐developed reverse‐hybridization assay in the South African population

An unusual case of hemochromatosis due to a new compound heterozygosity in HFE (p.[Gly43Asp;His63Asp]+[Cys282Tyr]): structural implications with respect to binding with transferrin receptor 1

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