A Novel Phenotype of a Hereditary Hemochromatosis Type 4 with Ferroportin-1 Mutation, Presenting with Juvenile Cataracts

Yamakawa, Naoyuki; Oe, Kengo; Yukawa, Naoichiro; Murakami, Kosaku; Nakashima, Ran; Imura, Yoshitaka; Yoshifuji, Hajime; Ohmura, Koichiro; Miura, Yasuo; Tomosugi, Naohisa; Kawabata, Hiroshi; Takaori‐Kondo, Akifumi; Mimori, Tsuneyo

doi:10.2169/internalmedicine.55.6565

Cited by 10 publications

(8 citation statements)

References 18 publications

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“…We examined the structural and functional characteristics of clinical gain-of-function Fpn mutants associated with both hyperferritinemia and transferrin saturation .60% (Table 1 [11][12][13][14][15][16][17][18][19][20][21][22][23][24] ). Additional nonclinical mutants were generated to probe the hepcidin-binding region in greater detail.…”

Section: Introductionmentioning

confidence: 99%

Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin

Aschemeyer¹,

Qiao²,

Stefanova

et al. 2018

Blood

261

216

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Nonclassical ferroportin disease (FD) is a form of hereditary hemochromatosis caused by mutations in the iron transporter ferroportin (Fpn), resulting in parenchymal iron overload. Fpn is regulated by the hormone hepcidin, which induces Fpn endocytosis and cellular iron retention. We characterized 11 clinically relevant and 5 nonclinical Fpn mutations using stably transfected, inducible isogenic cell lines. All clinical mutants were functionally resistant to hepcidin as a consequence of either impaired hepcidin binding or impaired hepcidin-dependent ubiquitination despite intact hepcidin binding. Mapping the residues onto 2 computational models of the human Fpn structure indicated that (1) mutations that caused ubiquitination-resistance were positioned at helix-helix interfaces, likely preventing the hepcidin-induced conformational change, (2) hepcidin binding occurred within the central cavity of Fpn, (3) hepcidin interacted with up to 4 helices, and (4) hepcidin binding should occlude Fpn and interfere with iron export independently of endocytosis. We experimentally confirmed hepcidin-mediated occlusion of Fpn in the absence of endocytosis in multiple cellular systems: HEK293 cells expressing an endocytosis-defective Fpn mutant (K8R), oocytes expressing wild-type or K8R Fpn, and mature human red blood cells. We conclude that nonclassical FD is caused by Fpn mutations that decrease hepcidin binding or hinder conformational changes required for ubiquitination and endocytosis of Fpn. The newly documented ability of hepcidin and its agonists to occlude iron transport may facilitate the development of broadly effective treatments for hereditary iron overload disorders.

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Section: Introductionmentioning

confidence: 99%

Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin

Aschemeyer¹,

Qiao²,

Stefanova

et al. 2018

Blood

261

216

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“…Thus, it seems to be reasonable that the present patient with a mutation of p.H507R in SLC40A1 exhibited nonclassical ferroportin disease. To the best of our knowledge, based on the literature, the present case is the fifth reported patient with mutant ferroportin p.H507R and the third family lineage in the world [ 11 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…The increase in iron levels and inflammation upregulate the transcription of the HAMP gene [ 16 – 19 ]. HJV, HFE, TRF1, and TFR2, which are located at the surface of hepatocytes, are considered to be “iron sensors.” The HJV-hepcidin axis is the most important mechanism for the upregulation of HAMP expression during iron overload [ 15 ]. In this patient, the increased levels of both ferritin and hepcidin-25 in serum suggested that hepcidin secretion was properly regulated, which was consistent with another Japanese patient with mutant ferroportin p.H507R [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…HJV, HFE, TRF1, and TFR2, which are located at the surface of hepatocytes, are considered to be “iron sensors.” The HJV-hepcidin axis is the most important mechanism for the upregulation of HAMP expression during iron overload [ 15 ]. In this patient, the increased levels of both ferritin and hepcidin-25 in serum suggested that hepcidin secretion was properly regulated, which was consistent with another Japanese patient with mutant ferroportin p.H507R [ 15 ]. In addition, we have reported for the first time that serum hepcidin-25 levels can return to the normal range after reduction in hepatic iron accumulation by phlebotomy in this patient.…”

Section: Discussionmentioning

confidence: 99%

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Long-term phlebotomy successfully alleviated hepatic iron accumulation in a ferroportin disease patient with a mutation in SLC40A1: a case report

et al. 2021

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Background Hereditary hemochromatosis is a heterogenous group of inherited iron-overload conditions that is characterized by increased intestinal absorption and deposition in vital organs. Hepcidin is a soluble regulator that acts to attenuate both intestinal iron absorption and iron release from reticuloendothelial macrophages through internalization of ferroportin-1, an iron exporter. Ferroportin disease is hereditary hemochromatosis which is affected by SLC40A1, a gene coding ferroportin-1, and phenotypically classified into two forms (classical and nonclassical). In nonclassical form, ferroportin mutations are responsible for a gain of function with full iron export capability but insensitivity to downregulation by hepcidin. Here, we report a case of nonclassical ferroportin disease. Case presentation A 46-year-old Japanese man showed elevated serum iron (284 μg/dl), ferritin (1722 ng/ml), transferrin saturation ratio (91.3%), and hepcidin-25 level (139.6 ng/ml). Magnetic resonance imaging (MRI) demonstrated a marked reduction in the signal intensity of the liver in T1- and T2-weighted images. The liver histology exhibited a large amount of iron that had accumulated predominantly in hepatocytes. We identified a heterozygous 1520A > G (p.H507R) mutation in the SLC40A1 gene. Phlebotomy (400 ml at a time) was monthly performed for 3 years in this patient. Importantly, the serum hepcidin level (1.0 ng/ml) was normal when the serum ferritin level was normal and hepatic iron accumulation was remarkably reduced after 3 years of phlebotomy. Conclusions The present case demonstrated for the first time that there was a correlation between hepatic iron levels as measured by MRI and serum hepcidin levels through long-term phlebotomy in a patient with ferroportin disease with the p.H507R mutation of in SLC40A1.

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“…HH type 4A has distinctive clinical features such as a low transferrin saturation and marginal anemia with low tolerance to phlebotomy [76]. We previously described a Japanese family with HH type 4B and juvenile cataract, though the mechanism of the development of early-onset cataract in this family was undetermined [122].…”

Section: Manifestations Of Hhmentioning

confidence: 98%

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

Kawabata

2017

Int J Hematol

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Hereditary hemochromatosis (HH) is a group of genetic iron overload disorders that manifest with various symptoms, including hepatic dysfunction, diabetes, and cardiomyopathy. Classic HH type 1, which is common in Caucasians, is caused by bi-allelic mutations of HFE. Severe types of HH are caused by either bi-allelic mutations of HFE2 that encodes hemojuvelin (type 2A) or HAMP that encodes hepcidin (type 2B). HH type 3, which is of intermediate severity, is caused by bi-allelic mutations of TFR2 that encodes transferrin receptor 2. Mutations of SLC40A1 that encodes ferroportin, the only cellular iron exporter, causes either HH type 4A (loss-of-function mutations) or HH type 4B (gain-of-function mutations). Studies on these gene products uncovered a part of the mechanisms of the systemic iron regulation; HFE, hemojuvelin, and TFR2 are involved in iron sensing and stimulating hepcidin expression, and hepcidin downregulates the expression of ferroportin of the target cells. Phlebotomy is the standard treatment for HH, and early initiation of the treatment is essential for preventing irreversible organ damage. However, because of the rarity and difficulty in making the genetic diagnosis, a large proportion of patients with non-HFE HH might have been undiagnosed; therefore, awareness of this disorder is important.

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A Novel Phenotype of a Hereditary Hemochromatosis Type 4 with Ferroportin-1 Mutation, Presenting with Juvenile Cataracts

Cited by 10 publications

References 18 publications

Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin

Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin

Long-term phlebotomy successfully alleviated hepatic iron accumulation in a ferroportin disease patient with a mutation in SLC40A1: a case report

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

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