HJV – Hereditary Hemochromatosis

Hemojuvelin (encoded by HJV; HGNC:4887) is a glycosylphosphatidylinositol-anchored BMP co-receptor critical for hepcidin induction. Bi-allelic loss-of-function variants in HJV cause autosomal recessive juvenile hemochromatosis, a severe form of hereditary hemochromatosis (MONDO:0006507) characterized by early-onset iron overload in liver, heart, pancreas, and endocrine organs (e.g., hypogonadism, skin hyperpigmentation).

Genetic evidence for HJV–hereditary hemochromatosis includes multiple unrelated probands with biallelic pathogenic variants. Two siblings homozygous for c.265T>C (p.Cys89Arg) presented with juvenile hemochromatosis, while their brother died from probable hereditary hemochromatosis in early adulthood (PMID:24872867). A systematic review of 132 HJV-related hemochromatosis cases (117 biallelic) across diverse ethnicities further established the broad variant spectrum and genotype-phenotype correlation, with recurrent G320V and L101P alleles in Caucasians (PMID:31286966).

Segregation analysis in family studies confirms recessive inheritance: c.265T>C (p.Cys89Arg) segregated in two affected siblings (PMID:24872867). Additional reports of homozygous and compound heterozygous HJV mutations in separate pedigrees lend further support.

Functional assays demonstrate that HJV pathogenic variants disrupt hepcidin regulation by impairing protein maturation and membrane localization. Mutants such as p.Gly320Val and p.Arg326Ter are retained in the endoplasmic reticulum and fail to up-regulate the HAMP promoter, confirming a loss-of-function mechanism in juvenile hemochromatosis (PMID:17264300; PMID:17768121).

While most evidence supports a strong recessive association, heterozygous HJV variants have been reported in adult-onset non-classic hemochromatosis, suggesting possible modifier roles but not primary causation. No studies have formally refuted the HJV–hereditary hemochromatosis link.

Integration of genetic and functional data indicates a Strong gene-disease association: HJV variants reliably predict juvenile hemochromatosis risk and guide early intervention. Key take-home: HJV genetic testing is essential for diagnosis of non-HFE hereditary hemochromatosis and informs treatment timing to prevent irreversible organ damage.

References

• Middle East journal of digestive diseases • 2014 • Juvenile Hemochromatosis, Genetic Study and Long-term Follow up after Therapy. PMID:24872867
• Orphanet journal of rare diseases • 2019 • Genotypic and phenotypic spectra of hemojuvelin mutations in primary hemochromatosis patients: a systematic review. PMID:31286966
• 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

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