HJV – Juvenile Hemochromatosis Type 2

Juvenile hemochromatosis type 2 (JH2) is a severe, early-onset iron overload disorder resulting from biallelic pathogenic variants in the HJV gene. Hemojuvelin (HJV) encodes a glycosylphosphatidylinositol-anchored BMP co-receptor that up-regulates hepcidin transcription in hepatocytes. Loss of HJV function leads to hepcidin deficiency and unrestrained dietary iron absorption, culminating in organ iron deposition, particularly in the heart, liver and endocrine glands ([PMID:14647275]). Clinically, JH2 presents before age 30 with hypogonadotropic hypogonadism, cardiomyopathy, hepatic fibrosis and diabetes mellitus. Early molecular diagnosis enables prompt iron removal by phlebotomy or chelation to prevent irreversible damage.

Genetic evidence supports an autosomal recessive inheritance of JH2, with consanguineous and nonconsanguineous families exhibiting homozygous or compound heterozygous HJV variants. To date, over 34 probands have been reported with biallelic HJV mutations ([PMID:14982873]), including segregation in at least four independent kinships ([PMID:14982867], [PMID:14982873]). The most recurrent variant, c.959G>T (p.Gly320Val), accounts for approximately two-thirds of cases in European and Irish cohorts ([PMID:14647275], [PMID:15967692]). Segregation of c.862C>T (p.Arg288Trp) in two affected siblings from a consanguineous kindred further confirms pathogenicity ([PMID:15315789]).

The HJV variant spectrum comprises predominantly loss-of-function alleles—nonsense, frameshift or splice-site mutations—and missense changes affecting conserved residues in the von Willebrand domain. Among the 17 mutations identified in a cohort of 34 patients, 13 were missense substitutions (e.g., p.Cys80Arg, p.Leu101Pro, p.Arg176Cys) and 9 were predicted to truncate HJV (e.g., p.Arg326Ter, p.Asp256fs) ([PMID:14982873]). Founder and recurrent alleles such as p.Gly320Val have been observed across ethnicities, indicating mutational hotspots and reinforcing the need for targeted screening in suspected JH2.

Functional assays in cell culture and animal models delineate a haploinsufficiency mechanism. Mutant HJV proteins (p.Arg326Ter, p.Cys119Phe, p.Gly320Val) exhibit defective proteolytic processing, retention in the endoplasmic reticulum and impaired plasma membrane localization, abrogating BMP-SMAD signaling and hepcidin promoter activation ([PMID:17264300], [PMID:17768121]). Neo1-deficient hepatocyte models demonstrate that HJV–Neogenin interaction is essential for hepcidin induction, while Hjv–/– mice recapitulate the iron overload phenotype ([PMID:33824974]). Iron chelation and phlebotomy in patients with homozygous p.Ile281Thr successfully normalized ferritin levels and preserved organ function ([PMID:32824233]).

No convincing reports dispute the HJV–JH2 association. Rare heterozygous HJV variants without additional risk factors do not produce the full JH2 phenotype, underscoring the recessive inheritance. Modifier genes in the BMP–SMAD pathway may modulate expressivity but have not refuted the core genotype–phenotype relationship.

In summary, robust genetic and experimental data classify the HJV–juvenile hemochromatosis type 2 relationship as Strong. Pathogenic HJV variants cause hepcidin deficiency and severe early-onset iron overload. Early genetic testing followed by iron removal therapy is critical to prevent fatal cardiomyopathy and endocrine failure.

References

• Nature Genetics • 2004 • Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis PMID:14647275
• Blood • 2004 • Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis PMID:14982873
• Blood • 2004 • Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin PMID:14982867
• Blood • 2007 • Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis PMID:17264300
• Haematologica • 2007 • Phenotypic and functional data confirm causality of the recently identified hemojuvelin p.R176C missense mutation PMID:17768121
• Journal of medical case reports • 2018 • Reversal of end-stage heart failure in juvenile hemochromatosis with iron chelation therapy: a case report PMID:29373985

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