Hemojuvelin

Hemojuvelin (HJV), also known as repulsive guidance molecule C (RGMc) or hemochromatosis type 2 protein (HFE2), is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as

For many years the signal transduction pathways that regulate systemic iron homeostasis have been unknown. However it has been demonstrated that hemojuvelin interacts with

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.^[14][15]

A soluble form of HJV may be a molecule that suppresses hepcidin expression.^[16]

RGMs may play inhibitory roles in prostate cancer by suppressing cell growth, adhesion, migration and invasion. RGMs can coordinate Smad-dependent and Smad-independent signalling of BMPs in prostate cancer and breast cancer cells.^[17][18] Furthermore, aberrant expression of RGMs was indicated in breast cancer. The perturbed expression was associated with disease progression and poor prognosis.^[19]

Related gene problems

• TAR syndrome
• 1q21.1 deletion syndrome
• 1q21.1 duplication syndrome

Gene structure and transcription

RGMc/HJV is a 4-

RGMc/HJV, is transcriptionally regulated during muscle differentiation.[11]

Isoforms

Two classes of

• 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.[20]
• 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.^[20]

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.^[20]

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.^[21]

Structure

In 2009, the Rosetta ab initio protein structure prediction software has been used to create a three-dimensional model of the RGM family of proteins.,^[8] In 2011, a crystal structure of a fragment of hemojuvelin binding to neogenin was completed ^[22] showing similar structures to the ab initio model and further informing the view of the RGM family of proteins.

Mechanism of action

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.^[23][24]

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 (