Alternative titles; symbols
HGNC Approved Gene Symbol: HJV
SNOMEDCT: 35400008, 399053004, 399170009; ICD10CM: E83.110; ICD9CM: 275.01;
Cytogenetic location: 1q21.1 Genomic coordinates (GRCh38) : 1:146,017,470-146,021,735 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.1 | Hemochromatosis, type 2A | 602390 | Autosomal recessive | 3 |
By a positional cloning strategy, Papanikolaou et al. (2004) identified the HJV gene within the region associated with juvenile hemochromatosis on chromosome 1q21 (HFE2A; 602390). By Northern blot analysis of human tissues, Papanikolaou et al. (2004) found that hemojuvelin transcript expression was restricted to liver, heart, and skeletal muscle, similar to that of hepcidin (HAMP; 606464), a key protein implicated in iron metabolism that is mutant in juvenile hemochromatosis showing linkage to 19q. A primary 2.2-kb transcript was expressed in these tissues. Hemojuvelin is transcribed from a gene of 4,265 bp into a full-length transcript with 5 spliced isoforms. The putative full-length protein from the longest transcript has 426 amino acids. Hemojuvelin contains multiple protein motifs consistent with a function as a membrane-bound receptor or secreted polypeptide hormone.
Hemojuvelin is a coreceptor for bone morphogenetic proteins (BMPs; see 112264), and inhibition of endogenous BMP signaling reduces hepcidin expression and increases serum iron in mice (Babitt et al. (2006, 2007)). Using a protein pull-down assay, Andriopoulos et al. (2009) demonstrated a direct physical interaction between recombinant soluble human HJV and BMP6 (112266). Intraperitoneal injection of BMP6 in mice caused increased hepatic hepcidin mRNA expression and reduced serum iron and transferrin (190000) saturation in a dose-dependent manner. Conversely, inhibition of endogenous Bmp6 in mice reduced hepcidin expression and increased serum iron. Andriopoulos et al. (2009) concluded that BMP6 is an HJV ligand and an endogenous regulator of hepcidin expression and iron metabolism.
The HJV gene maps to chromosome 1q21 (Papanikolaou et al., 2004).
Papanikolaou et al. (2004) identified 6 different deleterious mutations in the HJV gene in 10 Greek families, 1 Canadian family, and 1 French family with juvenile hemochromatosis (HFE2A; 602390). One mutation, gly320 to val (G320V; 608374.0001), was observed in all 3 populations and accounted for two-thirds of the mutations found. The clinical and biochemical phenotype of juvenile hemochromatosis in families showing linkage to 1q (HFE2A) is indistinguishable from that in families showing linkage to 19q (HFE2B; 613313), in which the gene encoding hepcidin (HAMP; 606464) is mutant. Papanikolaou et al. (2004) found that deleterious mutations of hemojuvelin reduced hepcidin levels despite iron overload, which normally induces hepcidin expression. These and other results suggested that HJV acts as a modulator of hepcidin expression, although it was not possible to distinguish a pretranscriptional from a posttranscriptional or even posttranslational role for HJV in the absence of liver biopsies to measure hepcidin mRNA levels.
Lanzara et al. (2004) reviewed the spectrum of HJV gene mutations in 1q-linked juvenile hemochromatosis.
Lee et al. (2004) addressed the question of whether HJV mutations may influence the phenotype of patients with adult-onset hemochromatosis (235200) with or without mutations of the HFE gene (613609). They sequenced the complete coding sequence of HJV in 133 patients with iron overload. One patient with severe iron overload was found to be a compound heterozygote for HJV mutations: G320V (608374.0001) and cys321 to ter (C321W; 608374.0007).
Among 310 HFE patients with homozygosity for the C282Y mutation (613609.0001), Le Gac et al. (2004) found 9 patients with an additional heterozygous HJV mutation, including the previously described L101P (608374.0006) and G320V (608374.0001) mutations. Iron indices of 8 of these patients appeared to be more severe than those observed in sex- and age-matched C282Y homozygotes without an HJV mutation. Mean serum ferritin concentrations of the 6 males with an HJV mutation were significantly higher than those of C282Y homozygous males without an HJV mutation.
Wallace and Subramaniam (2016) reviewed 161 variants previously associated with any form of hereditary hemochromatosis and found that 43 were represented among next-generation sequence public databases including ESP, 1000 Genomes Project, and ExAC. The frequency of the C282Y mutation in HFE (613609.0001) matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2 (604720)-, HFE2-, and HAMP (606464)-related forms were extremely rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. However, SLC40A1 (604653) variants were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans.
Niederkofler et al. (2005) found that Hjv was expressed in mouse liver by periportal hepatocytes. Hjv -/- mice exhibited iron overload and failed to express hepcidin in response to dietary or injected iron. However, these mice retained the ability to upregulate hepcidin in response to acute inflammation induced by either lipopolysaccharide or its downstream products, Il6 (147620) and Tnf-alpha (TNF; 191160). In wildtype mice, induction of inflammation resulted in downregulation of Hjv expression in liver, but not in skeletal muscle. Niederkofler et al. (2005) concluded that downregulation of hepatic HJV during inflammation may induce a temporary elimination of iron sensing.
Huang et al. (2005) found that Hjv -/- mice rapidly accumulated iron in liver, pancreas, and heart, but had decreased iron content in spleen. In contrast to findings in human patients, Huang et al. (2005) detected no abnormalities in fertility and no obvious cardiac or endocrine abnormalities, suggesting that mice are more resistant to end-organ damage. Hepatic hepcidin expression was markedly decreased, and ferroprotein protein levels were elevated in intestinal epithelial cells and macrophages. Huang et al. (2005) proposed that juvenile hemochromatosis results from impaired hepcidin regulation and consequent overexpression of ferroprotein.
Lenoir et al. (2011) found that double knockout of Bmp6 and Tmprss6 (609862) in mice rescued the iron deficiency anemia observed in Tmprss6 -/- mice, although hepcidin expression was repressed to the same extent as in Bmp6 -/- mice. Heterozygous loss of Bmp6 in Tmprss6 -/- mice partly corrected systemic iron homeostasis by decreasing hepcidin gene expression and increasing plasma and liver iron levels. Lenoir et al. (2011) concluded that BMP6 is the physiologic ligand of HJV and that regulation of HJV membrane expression by TMPRSS6 tightly controls BMP6 signaling.
Jenkitkasemwong et al. (2015) found that loss of Slc39a14 prevented hepatic iron overload in the Hfe -/- and Hfe2 -/- mouse models of hemochromatosis. However, loss of Slc39a14 did not prevent iron accumulation in other tissues and cells of Hfe -/- or Hfe2 -/- mice, but instead resulted in altered patterns of iron accumulation compared with single-knockout or wildtype mice. Jenkitkasemwong et al. (2015) concluded that SLC39A14 is required for development of hepatic iron overload in hereditary hemochromatosis.
In 7 of 10 Greek families with juvenile hemochromatosis (HFE2A; 602390), Papanikolaou et al. (2004) identified a homozygous gly320-to-val (G320V) mutation in the HJV gene. Affected individuals shared the common Greek haplotype. This same mutation was found in 1 Canadian and 1 French family with juvenile hemochromatosis. In 1 Greek family, the G320V mutation was in compound heterozygous state with arg326 to ter (R326X; 608374.0002), and in 1 Canadian family, G320V was in compound heterozygous state with ile222 to asn (I222N; 608374.0003).
In a white female diagnosed with hereditary hemochromatosis (HFE1; 235200) at the age of 30 years when she presented with progressive fatigue and early onset of menopause, Lee et al. (2004) identified compound heterozygosity for mutations in the HJV gene: G320V and cys321 to trp (C321W; 608374.0007). Pituitary insufficiency was diagnosed, and deeply pigmented skin, elevated serum iron, and total iron binding capacity, as well as transferrin saturation, were found. The patient had had 2 normal pregnancies, the last when she was 21 years old; she developed amenorrhea at age 23 years. Her medical history also included hypothyroidism treated with thyroxine for most of her adult life. She also had had multiple dental problems since early adulthood, requiring a dental implant. She developed type II diabetes (125853) at age 59 years, which was controlled by an oral hypoglycemic agent.
In 17 patients with juvenile hemochromatosis (JH) from 12 families of the isolated region of Saguenay-Lac-Saint-Jean in Quebec, who were previously studied by Rivard et al. (2003), Lanzara et al. (2004) identified homozygosity for the G320V mutation. However, among 13 unrelated Italian JH patients in the study, the only G320V homozygote was likely of Greek ancestry, because he lived in a southern Italian region where a dialect resembling Greek was still spoken.
In 6 of 7 patients with JH from 6 unrelated central European families (from Germany, Slovakia, and Croatia), Gehrke et al. (2005) identified homozygosity for the G320V mutation in 4 patients and compound heterozygosity for G320V and a 4-bp deletion (608374.0008) in 2 patients. Gehrke et al. (2005) concluded that the genetic background of JH might be more homogeneous than initially believed. In a Croatian patient who had the most severe phenotype, with liver cirrhosis, severe dilated cardiomyopathy, and hypogonadism, Gehrke et al. (2005) also found a heterozygous C282Y mutation in the HFE gene (613609.0001) and suggested that HFE mutations might influence the phenotypic expression in HJV-related JH.
In a 21-year-old male patient with hemochromatosis who died due to low cardiac output and multiorgan failure, Brakensiek et al. (2009) identified homozygosity for the G320V mutation in the HJV gene, as well as compound heterozygosity for the H63D (613609.0002) and S65C (613609.0003) mutations in the HFE gene. Brakensiek et al. (2009) suggested that severity of the clinical course in this patient might be related to the complex genotype.
For discussion of the arg326-to-ter (R326X) mutation in the HJV gene that was found in compound heterozygous state in patients with juvenile hemochromatosis (HFE2A; 602390) by Papanikolaou et al. (2004), see 608374.0001.
For discussion of the ile222-to-asn (I222N) in the HJV gene that was found in compound heterozygous state in patients with juvenile hemochromatosis (HFE2A; 602390) by Papanikolaou et al. (2004), see 608374.0001.
In a Greek family, Papanikolaou et al. (2004) found that 1 individual with juvenile hemochromatosis (HFE2A; 602390) was homozygous for an ile281-to-thr (I281T) mutation in the HJV gene.
For discussion of the I281T mutation in the HJV gene that was found in compound heterozygous state in a patient with juvenile hemochromatosis by Huang et al. (2004), see 608374.0007.
In affected members of a kindred with juvenile hemochromatosis (HFE2A; 602390) previously reported by Barton et al. (2002), Lee et al. (2004) identified a 238T-C transition in the HJV gene, resulting in a cys80-to-arg (C80R) substitution, in compound heterozygosity with a 302T-C transition, resulting in a leu101-to-pro substitution (L101P; 608374.0006). Remarkably, in another branch of the family, affected members were homozygous for the L101P mutation.
For discussion of the leu101-to-pro (L101P) mutation in the HJV gene that was found in compound heterozygous state in patients with juvenile hemochromatosis (HFE2A; 602390) by Lee et al. (2004), see 608374.0005.
For discussion of the cys321-to-ter (C321X) mutation in the HJV gene that was found in compound heterozygous state in a patient with hereditary hemochromatosis (HFE1; 235200) by Lee et al. (2004), see 608374.0001.
In a 19-year-old student from China with juvenile hemochromatosis (HFE2A; 602390) who had a 1-week history of palpitations, chest pain, and dyspnea, Huang et al. (2004) identified compound heterozygosity for mutations in the HJV gene: a C321X mutation and an ile281-to-ter mutation (I281T; 608374.0004), inherited from the mother and father, respectively. The maternal HJV gene also contained a gln6-to-his (Q6H) variant in cis with C321X. Because they did not analyze population-specific controls for the Q6H variant, Huang et al. (2004) did not know whether it was functionally significant; however, they noted that this position is not conserved in the rat hemojuvelin protein. The patient's medical history was significant for psoriasis and secondary amenorrhea, with the onset of menses occurring at age 11 years and ceasing at age 14 years. Initial examination disclosed green-gray skin tone, hepatomegaly, and atrial fibrillation. Echocardiography revealed a dilated cardiomyopathy with an ejection fraction of 20%. The parents were not related. The father also had psoriasis.
In 2 Slovakian sibs with juvenile hemochromatosis (HFE2A; 602390), Gehrke et al. (2005) identified compound heterozygosity for the G320V (608374.0001) mutation and a 4-bp deletion at nucleotide 980 in the HJV gene, predicted to result in a premature termination codon at residue 337.
In an African American man with juvenile hemochromatosis (HFE2A; 602390), Murugan et al. (2008) identified a homozygous 160A-T transversion in exon 3 of the HJV gene, resulting in an arg54-to-ter (R54X) substitution in a highly conserved region. He had very early onset of the disease by age 4 and developed liver cirrhosis by age 23 years. However, cardiomyopathy and hypogonadotrophic hypogonadism were not present. His paternal grandparents came from Tobago and Grenada, and his maternal grandparents were from Trinidad and Grenada. There was no family history of consanguinity, iron overload, or Caucasian or white admixture. His parents and sister had normal iron phenotypes.
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Jenkitkasemwong, S., Wang, C.-Y., Coffey, R., Zhang, W., Chan, A., Biel, T., Kim, J.-S., Hojyo, S., Fukada, T., Knutson, M. D. SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis. Cell Metab. 22: 138-150, 2015. [PubMed: 26028554] [Full Text: https://doi.org/10.1016/j.cmet.2015.05.002]
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Murugan, R. C., Lee, P. L., Kalavar, M. R., Barton, J. C. Early age-of-onset iron overload and homozygosity for the novel hemojuvelin mutation HJV R54X (exon 3; c.160A-T) in an African American male of West Indies descent. Clin. Genet. 74: 88-92, 2008. [PubMed: 18492090] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01017.x]
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