Heterozygous Mutations in BMP6 Pro-peptide Lead to Inappropriate Hepcidin Synthesis and Moderate Iron Overload in Humans

Daher, Raed; Kannengiesser, Caroline; Houamel, Dounia; Lefèbvre, Thibaud; Bardou-Jacquet, Édouard; Ducrot, Nicolas; Kerguenec, Caroline de; Jouanolle, Anne–Marie; Robréau, Anne-Marie; Oudin, Claire; Gac, Gérald Le; Moulouel, Boualem; Loustaud‐Ratti, Véronique; Bédossa, Pierre; Valla, Dominique; Gouya, Laurent; Beaumont, Carole; Brissot, Pierre; Puy, Hervé; Karim, Zoubida; Tchernitchko, Dimitri

doi:10.1053/j.gastro.2015.10.049

Cited by 75 publications

(74 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…29 Increased iron levels further stimulate the expression of BMP6 (bone morphogenetic protein 6), a member of the TGFβ superfamily, whose genetic impairment causes severe iron overload in mice 30,31 and in patients. 32 BMP6 binds to the GPI-anchored receptor hemojuvelin (HJV) at the cell surface, 33 as well as to type 1 (ALK2 and ALK3 34 ) and type 2 (BMPR2 and ACTR2a 35 ) serine threonine kinase receptors. As a result, SMAD1/5/8 is phosphorylated and binds to SMAD4, which translocates to the nucleus to induce hepcidin transcription.…”

Section: Introductionmentioning

confidence: 99%

Pathophysiological consequences and benefits of HFE mutations: 20 years of research

Hollerer

Bachmann²,

Muckenthaler

2017

Haematologica

View full text Add to dashboard Cite

Mutations in the HFE (hemochromatosis) gene cause hereditary hemochromatosis, an iron overload disorder that is hallmarked by excessive accumulation of iron in parenchymal organs. The HFE mutation p.Cys282Tyr is pathologically most relevant and occurs in the Caucasian population with a carrier frequency of up to 1 in 8 in specific European regions. Despite this high prevalence, the mutation causes a clinically relevant phenotype only in a minority of cases. In this review, we summarize historical facts and recent research findings about hereditary hemochromatosis, and outline the pathological consequences of the associated gene defects. In addition, we discuss potential advantages of HFE mutations in asymptomatic carriers.

show abstract

Section: Introductionmentioning

confidence: 99%

Pathophysiological consequences and benefits of HFE mutations: 20 years of research

Hollerer

Bachmann²,

Muckenthaler

2017

Haematologica

View full text Add to dashboard Cite

show abstract

“…14,15 Moreover, heterozygous mutations in the BMP6 prodomain were recently linked to inappropriately low hepcidin levels and iron overload in humans. 16 Notably, liver Bmp6 messenger RNA (mRNA) expression is regulated by dietary iron and correlates with liver iron content in mice, whereas Bmp6 expression is not altered by iron in other tissues. [17][18][19][20][21] In addition, a neutralizing BMP6 antibody blunts hepcidin induction by a high iron diet, resulting in increased accumulation of tissue iron in mice.…”

mentioning

confidence: 99%

Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice

Canali

Zumbrennen-Bullough

Core

et al. 2017

Blood

173

206

View full text Add to dashboard Cite

• Endothelial Bmp6 conditional knockout mice exhibit hemochromatosis, whereas hepatocyte and macrophage Bmp6 conditional knockout mice do not.• Our data support a model in which EC Bmp6 has paracrine actions on hepatocyte hemojuvelin to regulate hepcidin production.Bone morphogenetic protein 6 (BMP6) signaling in hepatocytes is a central transcriptional regulator of the iron hormone hepcidin that controls systemic iron balance. How iron levels are sensed to regulate hepcidin production is not known, but local induction of liver BMP6 expression by iron is proposed to have a critical role. To identify the cellular source of BMP6 responsible for hepcidin and iron homeostasis regulation, we generated mice with tissue-specific ablation of Bmp6 in different liver cell populations and evaluated their iron phenotype. Efficiency and specificity of Cre-mediated recombination was assessed by using Cre-reporter mice, polymerase chain reaction of genomic DNA, and quantitation of Bmp6 messenger RNA expression from isolated liver cell populations. Localization of the BMP co-receptor hemojuvelin was visualized by immunofluorescence microscopy. Analysis of the Bmp6 conditional knockout mice revealed that liver endothelial cells (ECs) expressed Bmp6, whereas resident liver macrophages (Kupffer cells) and hepatocytes did not. Loss of Bmp6 in ECs recapitulated the hemochromatosis phenotype of global Bmp6 knockout mice, whereas hepatocyte and macrophage Bmp6 conditional knockout mice exhibited no iron phenotype. Hemojuvelin was localized on the hepatocyte sinusoidal membrane immediately adjacent to Bmp6-producing sinusoidal ECs. Together, these data demonstrate that ECs are the predominant source of BMP6 in the liver and support a model in which EC BMP6 has paracrine actions on hepatocyte hemojuvelin to regulate hepcidin transcription and maintain systemic iron homeostasis. (Blood. 2017;129(4):405-414) IntroductionIron homeostasis is tightly controlled to ensure sufficient iron for erythropoiesis and other fundamental metabolic processes and to prevent the toxicity of excess iron.1 The peptide hormone hepcidin is a master regulator of systemic iron balance by mediating the degradation of the iron export protein ferroportin to limit dietary iron absorption and macrophage iron recycling.2 Hepcidin production in the liver is carefully titrated in response to changes in organismal iron content and iron utilization requirements.1 Failure to appropriately induce hepcidin in response to iron is a central feature of hereditary hemochromatosis, a genetic disorder characterized by excess iron deposits in the liver, heart, and endocrine glands, resulting in organ dysfunction. 3 The most severe juvenile-onset form of this disease is caused by mutations in the genes encoding hepcidin itself (HAMP) or hemojuvelin (HFE2, also known as HJV), which regulates hepcidin transcription in hepatocytes. 4,5 Mice with global or hepatocyte-specific deletion of these genes have a similar iron overload phenotype, 6-11 confirming the essential role of hepat...

show abstract

“…The heterozygous mutation of SLC40A1 Q248H is frequently observed in African populations and is associated with mild microcytic anemia and the tendency to iron overload [79,80]. Recently, families of HH harboring mutations in the propeptide of the BMP6 gene have been reported [81,82]. According to these studies, serum hepcidin levels of patients with heterozygous mutations of this gene were markedly low or inappropriately low for the iron overload.…”

Section: Various Types Of Hhmentioning

confidence: 99%

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

Kawabata

2017

Int J Hematol

View full text Add to dashboard Cite

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.

show abstract

Heterozygous Mutations in BMP6 Pro-peptide Lead to Inappropriate Hepcidin Synthesis and Moderate Iron Overload in Humans

Abstract: We identified 3 heterozygous missense mutations in BMP6 in patients with unexplained iron overload. These mutations lead to loss of signaling to SMAD proteins and reduced hepcidin production. These mutations might increase susceptibility to mild-to-moderate late-onset iron overload.

Cited by 75 publications

References 39 publications

Pathophysiological consequences and benefits of HFE mutations: 20 years of research

Pathophysiological consequences and benefits of HFE mutations: 20 years of research

Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice

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

Contact Info

Product

Resources

About