DENND3 p.L708V activating variant is involved in the pathogenesis of hereditary hemochromatosis via the RAB12/TFR2 signaling pathway
DENND3 p.L708V activating variant is involved in the pathogenesis of hereditary hemochromatosis via the RAB12/TFR2 signaling pathway
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DOI：
10.1007/s12072-022-10474-w
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发表时间：
2023-02
影响因子：
6.6
通讯作者：
Yanmeng Li;A. Xu;Ouyang Qin;Wei Zhang;Chunpan Zhang;Zhibin Chen;Donghu Zhou;Bei Zhang;W. Duan;Xinyan Zhao;Xiaoming Wang;H. You;X. Ou;J. Jia;Jian Huang
中科院分区：
文献类型：
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作者：
Yanmeng Li;A. Xu;Ouyang Qin;Wei Zhang;Chunpan Zhang;Zhibin Chen;Donghu Zhou;Bei Zhang;W. Duan;Xinyan Zhao;Xiaoming Wang;H. You;X. Ou;J. Jia;Jian Huang
目的在遗传性血色素沉着症（HH）的不同患者群体中已经发现了hfe和非hfe基因的致病变异，但仍有相当比例的患者存在不明原因的原发性铁超载。我们最近在中国不明原因的原发性铁超载患者中发现了正常和肿瘤细胞结构域3 （DENND3）基因差异表达的p.L708V复发变异体，该基因作为小GTpase Rab12的鸟嘌呤核苷酸交换因子，下调小鼠TfR表达。我们的目的是研究dennd3p的致病性和潜在的机制。HH患者的L708V变异。方法对原发性铁超载患者进行dennd3p . l708v分析。在携带dennd3p . l708v的HH患者中检测肝脏中TFR2和hepcidin的表达。dennd3p的影响。在体外和体内研究L708V对RAB12/TFR2及下游铁代谢途径的影响。结果31例HH患者中有6例（19.35%）存在dennd3p。L708V变体。服用dennd3p . l708v的HH患者肝脏中TFR2和hepcidin的表达降低。转染了dennd3p的细胞。L708V载体上调RAB12表达和溶酶体中TFR2降解，下调pSMAD1/5和hepcidin。表达dennd3p的腺相关病毒感染小鼠模型。L708V变异体表现为血清总铁浓度升高，hamp水平降低，铁积累量增加，肝脏TFR2表达下调。结论DENND3 p.L708V激活变异体通过DENND3/RAB12/TFR2轴下调hepcidin的表达，可能是HH潜在的新致病因子。
PurposePathogenic variants inHFEand non-HFEgenes 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 theDENND3p.L708V variant in HH patients.MethodsPatients with primary iron overload were analyzed forDENND3p.L708V. TFR2 and hepcidin expression in livers were examined in HH patients harboringDENND3p.L708V. The effects ofDENND3p.L708V on RAB12/TFR2 and downstream iron metabolic pathways were investigated in vitro and in vivo.ResultsSix of 31 patients with HH (19.35%) harbored theDENND3p.L708V variant. The expression of TFR2 and hepcidin was decreased in the liver of HH patients withDENND3p.L708V. Cells transfected with theDENND3p.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 expressingDENND3p.L708V variant showed higher total serum iron concentrations and decreasedHAMPlevel, increased amount of iron accumulation and the down-regulated of TFR2 expression in the liver.ConclusionsThe 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.