HFE和非HFE基因的病原变异已被鉴定为不同患者群体中遗传性血色素异常症（HH）的原因，但仍然有相当比例的患者出现原发性铁过载无法解释的情况。我们最近发现，中国患有原发性铁过载的患者中，存在一种不断重复的p.L708V变异，位于差异表达于正常细胞和肿瘤细胞域3（DENND3）基因上，其在小的GTPase Rab12的核苷酸交换因子中起作用，使其在小鼠中下调TfR表达。我们旨在研究DENND3 p.L708V变异在HH患者中的致病性和潜在机制。对原发性铁过载患者进行了DENND3 p.L708V的分析。HH患者的肝脏中TFR2和hepcidin表达进行了检查，并搜寻DENND3 p.L708V在RAB12/TFR2和下游铁代谢途径中的影响。在31名HH患者中，有6人（19.35％）携带DENND3 p.L708V变异。HH患者的肝脏中，携带DENND3 p.L708V变异的患者，TFR2和hepcidin的表达均下降。转染DENND3 p.L708V载体的细胞显示RAB12表达上调和TFR2降解，以及pSMAD1/5和hepcidin的下调。被潜在激活的DENND3 p.L708V变异通过DENND3/RAB12/TFR2轴下调hepcidin表达，这可能代表了HH的一个潜在的新的病因因素。 © 2023.亚太肝病研究学会。

Pathogenic variants in HFE and non-HFE genes have been identified in hereditary hemochromatosis (HH) in different patient populations, but there are still a considerable proportion of patients with unexplained primary iron overload. We recently identified in Chinese patients with unexplained primary iron overload a recurrent p.L708V variant in the differentially expressed in normal and neoplastic cells domain 3 (DENND3) gene, functioning as a guanine nucleotide exchange factor for small GTpase Rab12 which down-regulates TfR expression in mice. We aim to investigate the pathogenicity and the underlying mechanism of the DENND3 p.L708V variant in HH patients.Patients with primary iron overload were analyzed for DENND3 p.L708V. TFR2 and hepcidin expression in livers were examined in HH patients harboring DENND3 p.L708V. The effects of DENND3 p.L708V on RAB12/TFR2 and downstream iron metabolic pathways were investigated in vitro and in vivo.Six of 31 patients with HH (19.35%) harbored the DENND3 p.L708V variant. The expression of TFR2 and hepcidin was decreased in the liver of HH patients with DENND3 p.L708V. Cells transfected with the DENND3 p.L708V vector showed up-regulation of RAB12 expression and TFR2 degradation in lysosomes, and down-regulation of the pSMAD1/5 and hepcidin. Mice models infected with adeno-associated virus expressing DENND3 p.L708V variant showed higher total serum iron concentrations and decreased HAMP level, increased amount of iron accumulation and the down-regulated of TFR2 expression in the liver.The DENND3 p.L708V activating variant down-regulates hepcidin expression through the DENND3/RAB12/TFR2 axis, which may represent a potential novel pathogenic factor of HH.© 2023. Asian Pacific Association for the Study of the Liver.