Non-classical hereditary hemochromatosis in Portugal: novel mutations identified in iron metabolism-related genes

Mendes, Ana Isabel; Ferro, Ana; Martins, Rute; Picanço, Isabel; Gomes, Susana; Cerqueira, Rute; Correia, Manuel; Nunes, António Robalo; Esteves, J; Fleming, Rita; Faustino, Paula

doi:10.1007/s00277-008-0572-y

Cited by 39 publications

(32 citation statements)

References 36 publications

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“…The first two cases of JH due to homozygosity for this mutation were reported by Matthes and co-workers [12] in two Portuguese siblings. Then, another two JH patients were reported, also presenting homozygosity for the same mutation, in two unrelated families of North [13] and Centre of Portugal [8]. In this study, we report another two Portuguese siblings, with JH phenotype and homozygosity for the same mutation.…”

Section: Discussionmentioning

confidence: 64%

“…An extra set of five DNA samples previously analysed by Sanger sequencing and known to present a total 43 genetic alterations corresponding to 14 different genetic variants in HFE, TFR2, HAMP, and SLC40A1 [8] were used as positive controls: HFE (rs1799945, rs2071303, rs200706856, rs1572982, and rs1800758); TFR2 (rs41295912, rs148902192, rs80338885, and rs2075674); HAMP (c.-25GNA); SLC40A1 (rs2304704, rs4287798, rs1156835, and rs13008848).…”

Section: Sample Characterizationmentioning

confidence: 99%

“…Thirteen out of the mentioned 53 different identified variants were absent from the public databases (Table I). One of them, the HAMP (c.-25GNA), although not annotated in databases had been already found in the Portuguese population [8,12,13], and was considered a private variant. Among these 13 novel/private variants, five were predicted to be pathogenic by in silico studies and by genotype/phenotype correlation: three are missense mutations in HFE (p.Tyr 230Cys), and TFR2 (p.Leu750Pro and p.Ala777Val); one is a splicing mutation in TFR2 gene (c.967-1GNC); and one is located at the 5′-UTR of the HAMP gene (c.-25GN A).…”

Section: Patients' Genetic Variants Identification and Validationmentioning

confidence: 99%

“…Furthermore, in addition to the common HFE mutations, several rare variants of this gene have also been associated with HH [4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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Next-generation sequencing of hereditary hemochromatosis-related genes: Novel likely pathogenic variants found in the Portuguese population

Faria

Silva

et al. 2016

Blood Cells, Molecules, and Diseases

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Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive iron absorption resulting in pathologically increased body iron stores. It is typically associated with common HFE gene mutation (p.Cys282Tyr and p.His63Asp). However, in Southern European populations up to one third of HH patients do not carry the risk genotypes. This study aimed to explore the use of next-generation sequencing (NGS) technology to analyse a panel of iron metabolism-related genes (HFE, TFR2, HJV, HAMP, SLC40A1, and FTL) in 87 non-classic HH Portuguese patients. A total of 1241 genetic alterations were detected corresponding to 53 different variants, 13 of which were not described in the available public databases. Among them, five were predicted to be potentially pathogenic: three novel mutations in TFR2 [two missense (p.Leu750Pro and p.Ala777Val) and one intronic splicing mutation (c.967-1G NC)], one missense mutation in HFE (p.Tyr230Cys), and one mutation in the 5′-UTR of HAMP gene (c. -25GN A). The results reported here illustrate the usefulness of NGS for targeted iron metabolism-related gene panels, as a likely cost-effective approach for molecular genetics diagnosis of non-classic HH patients. Simultaneously, it has contributed to the knowledge of the pathophysiology of those rare iron metabolism-related disorders.

show abstract

Section: Discussionmentioning

confidence: 64%

Section: Sample Characterizationmentioning

confidence: 99%

Section: Patients' Genetic Variants Identification and Validationmentioning

confidence: 99%

“…Furthermore, in addition to the common HFE mutations, several rare variants of this gene have also been associated with HH [4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Next-generation sequencing of hereditary hemochromatosis-related genes: Novel likely pathogenic variants found in the Portuguese population

Faria

Silva

et al. 2016

Blood Cells, Molecules, and Diseases

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show abstract

“…Mendes et al (19) reported a case with heterozygous mutations, namely, c.187C>G in the HFE gene and c.840C>G in the TFR2 gene, and alcoholic habits, which are responsible for iron overload disease. This double heterozygosity was also observed in our patient, without toxic habits, who presented an iron overload phenotype confirmed by MRI and liver biopsy.…”

mentioning

confidence: 99%

Mutations in HFE and TFR2 genes in a Spanish patient with hemochromatosis

Rueda

Grande

Fernández

et al. 2011

Rev. esp. enferm. dig.

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Iron overload disease has a wide variety of genotypes. The genetic study of this disease confirms its hereditary nature and enables us to provide genetic counseling for first-degree relatives. We performed magnetic resonance imaging and liver biopsy in an asymptomatic patient with more than 1,000 µg/L of serum ferritin and studied the genes involved in this condition. The phenotype of iron overload is confirmed by a predominantly periportal pattern of iron deposits in the liver suggestive of genetic disease. In the case we present the molecular study revealed a double heterozygosity for the mutations c.187C>G (p.H63D) and c.840C>G (p.F280L) in the HFE and transferrin receptor 2 (TFR2) genes, respectively.

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Huh-7: A human “hemochromatotic” cell line

2009

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Hereditary hemochromatosis (HC) is commonly associated with homozygosity for the cysteineto-tyrosine substitution at position 282 (C282Y) of the HFE protein. This mutation prevents HFE from binding beta 2 -microglobulin (beta 2 M) and reaching the cell surface. We have discovered that a widely used hepatoma cell line, Huh-7, carries a HFE mutation similar to that associated with human HC. By HFE gene sequencing of Huh-7 genomic DNA, we found a TAC nucleotide deletion (c. 691_693del) responsible for loss of a tyrosine at position 231 (p. Y231del) of the HFE protein. This mutation affects a conserved hydrophobic region in a loop connecting two beta strands that make up the alpha3 domain of HFE, not far from the 282 site. HFE was detected by western blot in HepG2 but not in Huh-7 cell membrane fractions. In WRL-68 cells expressing wild-type HFE, the HFE protein was largely found at the plasma membrane where it colocalizes with beta 2 M. On the contrary, the HFE-Y231del mutant, similarly to an exogenously expressed HFE-C282Y mutant, failed to reach the plasma membrane and did not colocalize with membrane-expressed beta 2 M. C282Y mutant HFE in HC is associated with inadequate hepcidin expression. We found that Huh-7 cells display lower hepcidin messenger RNA levels as compared to HepG2 cells, which carry a wild-type HFE. Interestingly, hepcidin messenger RNA levels increased significantly in Huh-7 cells stably expressing exogenous wild-type HFE at the plasma membrane.

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Non-classical hereditary hemochromatosis in Portugal: novel mutations identified in iron metabolism-related genes

Cited by 39 publications

References 36 publications

Next-generation sequencing of hereditary hemochromatosis-related genes: Novel likely pathogenic variants found in the Portuguese population

Next-generation sequencing of hereditary hemochromatosis-related genes: Novel likely pathogenic variants found in the Portuguese population

Mutations in HFE and TFR2 genes in a Spanish patient with hemochromatosis

Huh-7: A human “hemochromatotic” cell line

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