DENND3 – Hereditary Hemochromatosis

DENND3 has emerged as an important contributor to hereditary hemochromatosis (HH). Recent multi‐patient studies, including a cohort of 32 individuals with primary iron overload, have identified multiple likely pathogenic DENND3 variants. In particular, a recurrent activating variant, DENND3 p.L708V, was observed in 6 of 31 probands (PMID:36729283), supporting a strong gene‑disease association.

The overall gene‑disease validity is assessed as Strong. This is based on multiple independent analyses demonstrating that, across cohorts, several DENND3 variants occur in affected individuals with HH. In one study, 5 likely pathogenic variants were reported among the 32 patient cohort (PMID:34583728), and additional evidence comes from the recurrent DENND3 p.L708V finding (PMID:36729283).

Genetic evidence further underscores this association. The recurrent DENND3 p.L708V variant and other deleterious changes provide robust case‐level data. Although segregation data were not explicitly provided, case reports and series indicate that variant carriage is enriched among patients with HH, which is consistent with autosomal recessive inheritance (PMID:36729283).

Functional studies have demonstrated that the DENND3 p.L708V variant disrupts iron homeostasis through the DENND3/RAB12/TFR2 signaling axis. In vitro assays and mouse models revealed that this activating variant leads to increased RAB12 expression, enhanced degradation of TFR2, and consequential down‑regulation of hepcidin expression. These findings align well with the clinical phenotype observed in patients with HH (PMID:36729283).

No substantial conflicting evidence has been reported regarding the role of DENND3 in HH. While comprehensive segregation data are not available, the convergence of genetic findings and functional assays provides a coherent narrative supporting the gene’s involvement in the disease process.

Key take‑home: The integration of robust genetic evidence and consistent functional data confirms a strong association between DENND3 variants and hereditary hemochromatosis, supporting its diagnostic utility and potential in guiding therapeutic strategies.

References

• Hepatology International • 2023 • DENND3 p.L708V activating variant is involved in the pathogenesis of hereditary hemochromatosis via the RAB12/TFR2 signaling pathway PMID:36729283
• Orphanet Journal of Rare Diseases • 2021 • Correlation of genotype and phenotype in 32 patients with hereditary hemochromatosis in China PMID:34583728

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