Hemojuvelin
Encyclopedia
Hemojuvelin is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as juvenile hemochromatosis
in humans, a severe form of hemochromatosis. In humans, the hemojuvelin protein is encoded by the HFE2 gene
. HJV is also called RGMc, a member of a three gene family (in vertebrates) called the repulsive guidance molecule
s. Both RGMa
and RGMb
are found in the nervous system, while RGMc is found in skeletal muscle and the liver.
(BMP), possibly as a co-receptor, and may signal via the SMAD pathway to regulate hepcidin expression. Associations with BMP2
and BMP4 have been described.
Mouse HJV knock-out
models confirmed that HJV is the gene
responsible for juvenile hemochromatosis. Hepcidin levels in the liver are dramatically depressed in these knockout animals.
A soluble form of HJV may be a molecule that suppresses hepcidin expression.
gene in mammals that undergoes alternative RNA splicing
to yield 3 mRNAs with different 5’ untranslated regions (5’UTRs
). Gene transcription is induced during myoblast
differentiation, producing all 3 mRNAs. There are three critical promoter elements responsible for transcriptional activation in skeletal muscle (the tissue that has the highest level of RGMc expressesion per weight), comprising paired E-box
es, a putative Stat
and/or Ets
element, and a MEF2
site, and muscle transcription factors myogenin and MEF2C
stimulate RGMc promoter function in non-muscle cells. As these elements are conserved in RGMc genes from multiple species, these results suggest that RGMc has been a muscle-enriched gene throughout its evolutionary history.
-anchored and glycosylated
HJV molecules are targeted to the membrane and undergo distinct fates.
RGMc appears to undergo a complex processing that generates 2 soluble, single-chain forms, and two membrane-bound forms found as a (i) single-chain, and (ii) two-chain species which appears to be cleaved at a site within a partial von Willebrand factor
domain.
Using a combination of biochemical and cell-based approaches, it has demonstrated that BMP-2 could interact in biochemical assays with the single-chain HJV species, and also could bind to cell-associated HJV. Two mouse HJV amino acid substitution mutants, D165E and G313V (corresponding to human D172E and G320V), also could bind BMP-2, but less effectively than wild-type HJV, while G92V (human G99V) could not. In contrast, the membrane-spanning protein, neogenin, a receptor for the related molecule, RGMa, preferentially bound membrane-associated heterodimeric RGMc and was able to interact on cells only with wild-type RGMc and G92V. These results show that different isoforms of RGMc/HJV may play unique physiological roles through defined interactions with distinct signaling proteins and demonstrate that, in some disease-linked HJV mutants, these interactions are defective.
ab initio protein structure prediction software has been used to create a three dimensional model of the RGM family of proteins.
-like proprotein convertases (PPC) are responsible for conversion of 50 kDa HJV to a 40 kDa protein with a truncated COOH-terminus, at a conserved polybasic RNRR site. This suggests a potential mechanism to generate the soluble forms of HJV/hemojuvelin (s-hemojuvelin) found in the blood of rodents and humans.
) gene. The gene was positionally cloned. Hemojuvelin is highly expressed in skeletal muscle and heart, and to a lesser extent in the liver. One insight into the pathogenesis of juvenile hemochromatosis is that patients have low to undetectable urinary hepcidin
levels, suggesting that hemojuvelin is a positive regulator of hepcidin, the central iron
regulatory hormone. As a result, low hepcidin levels would result in increased intestinal iron absorption. Thus, HJV/RGMc appears to play a critical role in iron metabolism.
Juvenile hemochromatosis
Juvenile hemochromatosis is, as its name indicates, a form of hemochromatosis which emerges during youth.There are two forms:* "HFE2A" is associated with hemojuvelin...
in humans, a severe form of hemochromatosis. In humans, the hemojuvelin protein is encoded by the HFE2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. HJV is also called RGMc, a member of a three gene family (in vertebrates) called the repulsive guidance molecule
Repulsive guidance molecule
Repulsive Guidance Molecules are members of a three gene family composed of RGMa, RGMb, and RGMc ....
s. Both RGMa
RGMA
Repulsive guidance molecule A also known as RGMa is a protein that in humans is encoded by the RGMA gene.- Function :RGMa is a repulsive guidance molecule for retinal axons. Furthermore neogenin functions as a receptor for RGM. Neogenin overexpression and RGM downexpression in the developing...
and RGMb
RGMB
RGM domain family, member B, also known as RGMB, is a protein that in humans is encoded by the RGMB gene.- Function :RGMB is a glycosylphosphatidylinositol -anchored member of the repulsive guidance molecule family and contributes to the patterning of the developing nervous system...
are found in the nervous system, while RGMc is found in skeletal muscle and the liver.
Function
For many years the signal transduction pathways that regulate systemic iron homeostasis have been unknown. However it has been demonstrated that hemojuvelin interacts with bone morphogenetic proteinBone morphogenetic protein
Bone morphogenetic proteins are a group of growth factors also known as cytokines and as metabologens . Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue...
(BMP), possibly as a co-receptor, and may signal via the SMAD pathway to regulate hepcidin expression. Associations with BMP2
Bone morphogenetic protein 2
Bone morphogenetic protein 2 or BMP-2 belongs to the TGF-β superfamily of proteins.-Function:BMP-2 like other bone morphogenetic proteins, plays an important role in the development of bone and cartilage. It is involved in the hedgehog pathway, TGF beta signaling pathway, and in cytokine-cytokine...
and BMP4 have been described.
Mouse HJV knock-out
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
models confirmed that HJV is the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
responsible for juvenile hemochromatosis. Hepcidin levels in the liver are dramatically depressed in these knockout animals.
A soluble form of HJV may be a molecule that suppresses hepcidin expression.
Related gene problems
- TAR syndromeTAR syndromeTAR Syndrome is a rare genetic disorder that is characterized by the absence of the radius bone in the forearm, and a dramatically reduced platelet count...
- 1q21.1 deletion syndrome1q21.1 deletion syndrome1q21.1 deletion syndrome or 1q21.1 microdeletion is a rare aberration of chromosome 1. , the international rare chromosome disorder group, has 48 genetically confirmed registered cases of this deletion worldwide ....
- 1q21.1 duplication syndrome1q21.1 duplication syndrome1q21.1 duplication syndrome or 1q21.1 microduplication is a rare aberration of chromosome 1. , the international rare chromosome disorder group, has 38 genetically confirmed registered cases of this duplication worldwide ....
Gene structure and transcription
RGMc/HJV is a 4-exonExon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
gene in mammals that undergoes alternative RNA splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
to yield 3 mRNAs with different 5’ untranslated regions (5’UTRs
Five prime untranslated region
A messenger ribonucleic acid molecule codes for a protein through translation. The mRNA also contains regions that are not translated: in eukaryotes these include the 5' untranslated region, 3' untranslated region, 5' cap and poly-A tail....
). Gene transcription is induced during myoblast
Myoblast
A myoblast is a type of embryonic progenitor cell that gives rise to muscle cells .The muscle cells can be skeletal muscle, smooth muscle, and cardiac muscle....
differentiation, producing all 3 mRNAs. There are three critical promoter elements responsible for transcriptional activation in skeletal muscle (the tissue that has the highest level of RGMc expressesion per weight), comprising paired E-box
E-box
An E-box is a DNA sequence which usually lies upstream of a gene in a promoter region. It is a transcription factor binding site where the specific sequence of DNA, CANNTG, is recognized by proteins that can bind to it to help initiate its transcription. Once transcription factors bind to...
es, a putative Stat
STAT protein
The STAT protein regulates many aspects of growth, survival and differentiation in cells...
and/or Ets
ETS transcription factor family
In the field of molecular biology, the ETS family is one of the largest families of transcription factors and is unique to metazoans. There are 29 genes in humans, 28 in the mouse, 10 in Caenorhabditis elegans and 9 in Drosophila. The founding member of this family was identified as a gene...
element, and a MEF2
Mef2
In the field of molecular biology, myocyte enhancer factor-2 proteins are a family of transcription factors which through control of gene expression are important regulators of cellular differentiation and consequently play a critical role in embryonic development. In adult organisms, Mef2...
site, and muscle transcription factors myogenin and MEF2C
MEF2C
Myocyte-specific enhancer factor 2C also known as MADS box transcription enhancer factor 2, polypeptide C is a protein that in humans is encoded by the MEF2C gene. MEF2C is a transcription factor in the Mef2 family.-Genomics:...
stimulate RGMc promoter function in non-muscle cells. As these elements are conserved in RGMc genes from multiple species, these results suggest that RGMc has been a muscle-enriched gene throughout its evolutionary history.
Isoforms
Two classes of GPIGlycophosphatidylinositol
Glycosylphosphatidylinositol is a glycolipid that can be attached to the C-terminus of a protein during posttranslational modification...
-anchored and glycosylated
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
HJV molecules are targeted to the membrane and undergo distinct fates.
- Full-length HJV is released from the cell surface and accumulates in extracellular fluid, where its half-life exceeds 24 hours. There appears to be two potential soluble isoforms and two membrane-associated isoforms.
- The predominant membrane-associated isoform, a disulfide-linked two-chain form composed of N- and C-terminal fragments, is not found in the extracellular fluid, and is short-lived, as it disappears from the cell surface with a half-life of < 3 hours after interruption of protein synthesis.
RGMc appears to undergo a complex processing that generates 2 soluble, single-chain forms, and two membrane-bound forms found as a (i) single-chain, and (ii) two-chain species which appears to be cleaved at a site within a partial von Willebrand factor
Von Willebrand factor
von Willebrand factor is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic-uremic syndrome...
domain.
Using a combination of biochemical and cell-based approaches, it has demonstrated that BMP-2 could interact in biochemical assays with the single-chain HJV species, and also could bind to cell-associated HJV. Two mouse HJV amino acid substitution mutants, D165E and G313V (corresponding to human D172E and G320V), also could bind BMP-2, but less effectively than wild-type HJV, while G92V (human G99V) could not. In contrast, the membrane-spanning protein, neogenin, a receptor for the related molecule, RGMa, preferentially bound membrane-associated heterodimeric RGMc and was able to interact on cells only with wild-type RGMc and G92V. These results show that different isoforms of RGMc/HJV may play unique physiological roles through defined interactions with distinct signaling proteins and demonstrate that, in some disease-linked HJV mutants, these interactions are defective.
Structure
The RosettaRosetta@home
Rosetta@home is a distributed computing project for protein structure prediction on the Berkeley Open Infrastructure for Network Computing platform, run by the Baker laboratory at the University of Washington...
ab initio protein structure prediction software has been used to create a three dimensional model of the RGM family of proteins.
Mechanism of action
FurinFurin
Furin is a protein that in humans is encoded by the FURIN gene. It was named furin because it was in the upstream region of an oncogene known as FES. The gene was known as FUR and therefore the protein was named furin...
-like proprotein convertases (PPC) are responsible for conversion of 50 kDa HJV to a 40 kDa protein with a truncated COOH-terminus, at a conserved polybasic RNRR site. This suggests a potential mechanism to generate the soluble forms of HJV/hemojuvelin (s-hemojuvelin) found in the blood of rodents and humans.
Clinical significance
Mutations in HJV are responsible for the vast majority of juvenile hemochromatosis patients. A small number of patients have mutations in the hepcidin (HAMPHAMP
Hepcidin is a protein that in humans is encoded by the HAMP gene.The product encoded by this gene is involved in the maintenance of iron homeostasis, and it is necessary for the regulation of iron storage in macrophages, and for intestinal iron absorption...
) gene. The gene was positionally cloned. Hemojuvelin is highly expressed in skeletal muscle and heart, and to a lesser extent in the liver. One insight into the pathogenesis of juvenile hemochromatosis is that patients have low to undetectable urinary hepcidin
Hepcidin
Hepcidin is a peptide hormone produced by the liver. It was discovered in 2000, and appears to be the master regulator of iron homeostasis in humans and other mammals. In humans, HAMP is the gene that encodes for hepcidin.-Structure:...
levels, suggesting that hemojuvelin is a positive regulator of hepcidin, the central iron
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
regulatory hormone. As a result, low hepcidin levels would result in increased intestinal iron absorption. Thus, HJV/RGMc appears to play a critical role in iron metabolism.