Analysis of the human hephaestin gene and protein: comparative modelling of the N-terminus ecto-domain based upon ceruloplasmin

Syed, Basharut A.; Beaumont, Nick; Patel, Alpesh; Naylor, C.E.; Bayele, Henry K.; Joannou, Christopher L.; Rowe, Peter; Evans, Robert W.; Srai, Surjit Kaila

doi:10.1093/protein/15.3.205

Cited by 51 publications

(46 citation statements)

References 47 publications

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“…There are gender-related differences in the iron phenotypes of normal persons and in those with heritable iron overload disorders [8][9][10][11][12], and allele/haplotype frequency disparities between men and women with hemochromatosis and other disorders [13,14]. Ferroportin interacts with hephaestin, an X-linked iron transporter, to transport iron out of enterocytes [15,16]. Female mice produce more hepcidin mRNA and have higher iron levels in liver and spleen than male mice [17]; this could also account for sex-associated differences in the function of normal or abnormal ferroportin as an iron exporter.…”

Section: Discussionmentioning

confidence: 99%

Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

Rivers

Barton²,

Gordeuk

et al. 2007

Blood Cells, Molecules, and Diseases

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The ferroportin (FPN1) Q248H polymorphism has been associated with increased serum ferritin (SF) levels in sub-Saharan Africans and in African Americans (AA). AA participants of the HEIRS Study who did not have HFE C282Y or H63D who had elevated initial screening SF (≥300 μg/L in men and ≥200 μg/L in women) (defined as cases) were frequency-matched to AA participants with normal SF (defined as controls) to investigate the association of the Q248H with elevated SF. 10.4% of cases and 6.7% of controls were Q248H heterozygotes (P = 0.257). Q248H homozygosity was observed in 0.5% of the cases and none of the controls. The frequency of Q248H was higher among men with elevated SF than among control men (P = 0.047); corresponding differences were not observed among women. This appeared to be unrelated to selfCorrespondence: Dr. James C. Barton G105, 2022 Brookwood Medical Center Drive Birmingham, AL 35209 Telephone 205-877-2888 FAX 205-877-2039 ironmd@dnamail.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. reports of a previous diagnosis of liver disease. Men with elevated SF were three times more likely than women with elevated SF to have Q248H (P = 0.012). There were no significant differences in Q248H frequencies in men and women control participants. We conclude that the frequency of the FPN1 Q248H polymorphism is greater in AA men with elevated SF than in those with normal SF. NIH Public Access

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Section: Discussionmentioning

confidence: 99%

Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

Rivers

Barton²,

Gordeuk

et al. 2007

Blood Cells, Molecules, and Diseases

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“…Hp is predicted to be a multicopper ferroxidase based on sequence similarity with Cp and conservation of structural features. 23 Copper is assembled into Cp in the Golgi 28 and it is reasonable to suggest copper is also incorporated into Hp at this point. Detection of Hp in Golgi may reflect this assembly process.…”

Section: Discussionmentioning

confidence: 99%

Mislocalisation of hephaestin, a multicopper ferroxidase involved in basolateral intestinal iron transport, in the sex linked anaemia mouse

Kuo

Su²,

Chen³

et al. 2004

Gut

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Background: Hephaestin is a multicopper ferroxidase required for basolateral transport of iron from enterocytes. Sex linked anaemia (sla) mice have a defect in the release of iron from intestinal enterocytes into the circulation due to an interstitial deletion in the hephaestin gene (heph). Results: We have demonstrated that hephaestin is primarily localised to a supranuclear compartment in both intestinal enterocytes and in cultured cells. In normal intestinal enterocytes, hephaestin was also present on the basolateral surface. In sla mice, hephaestin was present only in the supranuclear compartment. In contrast, the iron permease Ireg1 localised to the basolateral membrane in both control and sla mice. Conclusion: We suggest that mislocalisation of hephaestin likely contributes to the functional defect in sla intestinal epithelium.

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“…The A domains, which all share approximately 30% sequence identity among themselves, are homologous to the triplicate A domains present in factor V (FV) [2] and in ceruloplasmin (hCp) [3]. Murine hephaestin (He) [4] and haphaestin (Ha) [5] share a similar percentage of identity with human FVIII. Each of the two C domains shares the same homology with the discoidin protein family and with a mouse milk fat globule binding protein [6].…”

Section: Introductionmentioning

confidence: 99%

Small FVIII gene rearrangements in 18 hemophilia A patients: Five novel mutations

et al. 2005

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Hemophilia A (HA) is a disorder caused by mutations of the FVIII gene, which is located on the tip of the long arm of the X chromosome. In a cohort of 18 unrelated Italian patients affected with HA of varying severity, we performed mutational screening of the gene by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing of abnormal peaks. We identified five novel mutations and 9 previously reported DNA alterations. Two of the 9 previously reported alterations were each common to 3 unrelated patients. Six different mutations were characterized as missense alterations, while 8 were non-missense mutations. Among the new gene alterations, one created a stop codon, one consisted of an out-of frame deletion, and one was a splice-site mutation. The last two were missense alterations. In an attempt to better understand the causative effect of the mutations and the clinical variability of the patients, we investigated the consequences of each missense mutation and visualized the effect of the amino acid change on structural FVIII models. Am.

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Analysis of the human hephaestin gene and protein: comparative modelling of the N-terminus ecto-domain based upon ceruloplasmin

Cited by 51 publications

References 47 publications

Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

Mislocalisation of hephaestin, a multicopper ferroxidase involved in basolateral intestinal iron transport, in the sex linked anaemia mouse

Small FVIII gene rearrangements in 18 hemophilia A patients: Five novel mutations

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