Type 4B hereditary hemochromatosis due to heterozygous p.D157A mutation in SLC40A1 complicated with hypopituitarism

Honma, Yuichi; Karasuyama, Tsukasa; Kumamoto, Keiichiro; Shimajiri, Shohei; Toki, Yasumichi; Tatsumi, Yasuaki; Sumida, Kazuhiro; Koikawa, Kenji; Morino, Kahori; Oe, Shinji; Miyagawa, Koichiro; Yamasaki, Masahiro; Shibata, Michihiko; Abe, Shintaro; Ikuta, Katsuya; Hayashi, Hisao; Harada, Masaru

doi:10.1007/s00795-020-00259-1

Cited by 3 publications

(4 citation statements)

References 32 publications

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“…Anonymized information of the patients with the prehepatic class of ACP and ILA is summarized in Tables 1 and 2, 16,18,[30][31][32][33][34] and that of HC and SLC40A1-PIOSs is shown in Table 3. [16][17][18][19][20]22,24,25,[35][36][37][38][39][40] The clinical features of new patients in each disease category are described briefly, and the characteristics of each category are summarized in Table 4. [18][19][20][21]23 One of the five patients was newly enrolled in ACP of prehepatic PIOSs (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…Three patients with SLC40A1-PIOSs were reported in the first version 18 and five were newly enrolled in the revised version (Table 2). [36][37][38][39] Phenotypically, they were divided into five patients with SLC40A1-HC and three with FP-D. Four new patients with SLC40A1-HC were already complicated with multiorgan damage at presentation. All five patients with SLC40A1-HC had high serum ferritin and Hep25 levels and also had advanced chronic liver diseases associated with combined parenchymal and reticuloendothelial iron loading.…”

Section: Resultsmentioning

confidence: 99%

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A Revised Classification of Primary Iron Overload Syndromes

Tatsumi,

Yano,

Wakusawa

et al. 2024

J Clin Transl Hepatol

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Background and Aims:The clinical introduction of hep-cidin25 (Hep25) has led to a more detailed understanding of its relationship with ferroportin (FP) and divalent metal transporter1 in primary iron overload syndromes (PIOSs). In 2012, we proposed a classification of PIOSs based on the Hep25/FP system, which consists of prehepatic aceruloplasminemia, hepatic hemochromatosis (HC), and posthepatic FP disease (FP-D). However, in consideration of accumulated evidence on PIOSs, we aimed to renew the classification. Methods: We reviewed the 2012 classification and retrospectively renewed it according to new information on PIOSs. Results: Iron-loading anemia was included in PI-OSs as a prehepatic form because of the newly discovered erythroferrone-induced suppression of Hep25, and the state of traditional FP-D was remodeled as the BIOIRON proposal.The key molecules responsible for prehepatic PIOSs are low transferrin saturation in aceruloplasminemia and increased erythroferrone production by erythroblasts in iron-loading anemia. Hepatic PIOSs comprise four genotypes of HC, in each of which the synthesis of Hep25 is inappropriately reduced in the liver. Hepatic Hep25 synthesis is adequate in posthepatic PIOSs; however, two mutant FP molecules may resist Hep25 differently, resulting in SLC40A1-HC and FP-D, respectively. PIOS phenotypes are diagnosed using labora-tory tests, including circulating Hep25, followed by suitable treatments. Direct sequencing of the candidate genes may be outsourced to gene centers when needed. Laboratory kits for the prevalent mutations, such as C282Y, may be the first choice for a genetic analysis of HC in Caucasians. Conclusions: The revised classification may be useful worldwide.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A Revised Classification of Primary Iron Overload Syndromes

Tatsumi,

Yano,

Wakusawa

et al. 2024

J Clin Transl Hepatol

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“…Normally, hepcidin limits iron transport into plasma. But mutations in Slc40a1 disrupt the balance of plasma iron (Honma et al, 2021). In some patients with type 4 hemochromatosis, the loss of ferroportin function caused by Slc40a1 gene mutation was even detected (Anderson & Frazer, 2017).…”

Section: Slc40a1 and Diseasementioning

confidence: 99%

SLC40A1 in iron metabolism, ferroptosis, and disease: A review

Zhang,

Zou,

et al. 2024

WIREs Mechanisms of Disease

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Solute carrier family 40 member 1 (SLC40A1) plays an essential role in transporting iron from intracellular to extracellular environments. When SLC40A1 expression is abnormal, cellular iron metabolism becomes dysregulated, resulting in an overload of intracellular iron, which induces cell ferroptosis. Numerous studies have confirmed that ferroptosis is closely associated with the development of many diseases. Here, we review recent findings on SLC40A1 in ferroptosis and its association with various diseases, intending to explore new directions for research on disease pathogenesis and new therapeutic targets for prevention and treatment.This article is categorized under: Cancer > Genetics/Genomics/Epigenetics Metabolic Diseases > Molecular and Cellular Physiology

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“…Of note, all residues composing motif A (Gly80-Asp84-Arg88) and Asp157, which establish a network of interactions that stabilize the outward-open conformation of FPN, have been found to be mutated in patients, clearly indicating a critical role for conformational transitions in the iron transport cycle [ 56 , 59 ]. Variants Asp157Gly/Tyr/Asn are classified as loss-of-function, while the newly discovered Asp157Ala one appears to lead to a gain-of-function [ 60 ], highlighting the difficulty in predicting the effect of mutations. Gain-of-function mutations lead to resistance of FPN to hepcidin, either by the inability to bind the peptide in the central cavity of FPN in the outward conformation or by altering the internalization/ubiquitination process.…”

Section: Ferroportinmentioning

confidence: 99%

Membrane Transporters Involved in Iron Trafficking: Physiological and Pathological Aspects

et al. 2023

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Iron is an essential transition metal for its involvement in several crucial biological functions, the most notable being oxygen storage and transport. Due to its high reactivity and potential toxicity, intracellular and extracellular iron levels must be tightly regulated. This is achieved through transport systems that mediate cellular uptake and efflux both at the level of the plasma membrane and on the membranes of lysosomes, endosomes and mitochondria. Among these transport systems, the key players are ferroportin, the only known transporter mediating iron efflux from cells; DMT1, ZIP8 and ZIP14, which on the contrary, mediate iron influx into the cytoplasm, acting on the plasma membrane and on the membranes of lysosomes and endosomes; and mitoferrin, involved in iron transport into the mitochondria for heme synthesis and Fe-S cluster assembly. The focus of this review is to provide an updated view of the physiological role of these membrane proteins and of the pathologies that arise from defects of these transport systems.

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Type 4B hereditary hemochromatosis due to heterozygous p.D157A mutation in SLC40A1 complicated with hypopituitarism

Cited by 3 publications

References 32 publications

A Revised Classification of Primary Iron Overload Syndromes

A Revised Classification of Primary Iron Overload Syndromes

SLC40A1 in iron metabolism, ferroptosis, and disease: A review

Membrane Transporters Involved in Iron Trafficking: Physiological and Pathological Aspects

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