Identification of novel non-HFE mutations in Chinese patients with hereditary hemochromatosis
Abstract Backgrounds Hereditary hemochromatosis (HH) is mainly caused by homozygous p.C282Y mutations in HFE in the Caucasians. We recently reported non-HFE mutations constitute the major cause of HH in Chinese. However, there is still a relatively high proportion of cases with primary iron overload...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-06-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13023-022-02349-y |
| _version_ | 1818207833981714432 |
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| author | Wei Zhang Yanmeng Li Anjian Xu Qin Ouyang Liyan Wu Donghu Zhou Lina Wu Bei Zhang Xinyan Zhao Yu Wang Xiaoming Wang Weijia Duan Qianyi Wang Hong You Jian Huang Xiaojuan Ou Jidong Jia China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group |
| author_facet | Wei Zhang Yanmeng Li Anjian Xu Qin Ouyang Liyan Wu Donghu Zhou Lina Wu Bei Zhang Xinyan Zhao Yu Wang Xiaoming Wang Weijia Duan Qianyi Wang Hong You Jian Huang Xiaojuan Ou Jidong Jia China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group |
| author_sort | Wei Zhang |
| collection | DOAJ |
| description | Abstract Backgrounds Hereditary hemochromatosis (HH) is mainly caused by homozygous p.C282Y mutations in HFE in the Caucasians. We recently reported non-HFE mutations constitute the major cause of HH in Chinese. However, there is still a relatively high proportion of cases with primary iron overload from unexplained causes. We aimed to explore novel non-HFE mutations in Chinese patients with primary iron overload. Methods Whole exome sequence was conducted to screen mutations in novel HH-related genes in the 9 cases with unexplained primary iron overload. Then the representative candidate genes were screened for mutations in another cohort of 18 HH cases. The biological function of the selected genes and variants were analyzed in vitro. Results Whole exome sequencing of 9 cases with unexplained primary iron overload identified 42 missense variants in 40 genes associated with iron metabolism pathway genes such as UBE2O p.K689R and PCSK7 p.R711W. Subsequent Sanger sequencing of the UBE2O and PCSK7 genes in the 27 cases with primary iron overload identified p.K689R in UBE2O, p.R711W and p.V143F in PCSK7 at frequency of 2/27,1/27 and 2/27 respectively. In vitro siRNA interference of UBE2O and PCSK7 resulted in down-regulated HAMP mRNA expression. Adenovirus generation of UBE2O p.K689R in cell lines resulted in increased expression of SMAD6 and SMAD7 and downregulation of p-SMAD1/5 and HAMP expression, and the reduction of hepcidin level. Conclusions Our study identified a series of novel candidate non-HFE mutations in Chinese patients with HH. These may provide insights into the genetic basis of unexplained primary iron overload. |
| first_indexed | 2024-12-12T04:35:13Z |
| format | Article |
| id | doaj.art-aaeaf2706f0d4614bc303d1e038718fc |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-12T04:35:13Z |
| publishDate | 2022-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-aaeaf2706f0d4614bc303d1e038718fc2022-12-22T00:37:59ZengBMCOrphanet Journal of Rare Diseases1750-11722022-06-0117111210.1186/s13023-022-02349-yIdentification of novel non-HFE mutations in Chinese patients with hereditary hemochromatosisWei Zhang0Yanmeng Li1Anjian Xu2Qin Ouyang3Liyan Wu4Donghu Zhou5Lina Wu6Bei Zhang7Xinyan Zhao8Yu Wang9Xiaoming Wang10Weijia Duan11Qianyi Wang12Hong You13Jian Huang14Xiaojuan Ou15Jidong Jia16China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) GroupLiver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver CirrhosisNational Clinical Research Center for Digestive DiseasesNational Clinical Research Center for Digestive DiseasesNational Clinical Research Center for Digestive DiseasesLiver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver CirrhosisNational Clinical Research Center for Digestive DiseasesLiver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver CirrhosisNational Clinical Research Center for Digestive DiseasesLiver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver CirrhosisLiver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver CirrhosisLiver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver CirrhosisLiver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver CirrhosisLiver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver CirrhosisLiver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver CirrhosisLiver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver CirrhosisLiver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver CirrhosisLiver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver CirrhosisAbstract Backgrounds Hereditary hemochromatosis (HH) is mainly caused by homozygous p.C282Y mutations in HFE in the Caucasians. We recently reported non-HFE mutations constitute the major cause of HH in Chinese. However, there is still a relatively high proportion of cases with primary iron overload from unexplained causes. We aimed to explore novel non-HFE mutations in Chinese patients with primary iron overload. Methods Whole exome sequence was conducted to screen mutations in novel HH-related genes in the 9 cases with unexplained primary iron overload. Then the representative candidate genes were screened for mutations in another cohort of 18 HH cases. The biological function of the selected genes and variants were analyzed in vitro. Results Whole exome sequencing of 9 cases with unexplained primary iron overload identified 42 missense variants in 40 genes associated with iron metabolism pathway genes such as UBE2O p.K689R and PCSK7 p.R711W. Subsequent Sanger sequencing of the UBE2O and PCSK7 genes in the 27 cases with primary iron overload identified p.K689R in UBE2O, p.R711W and p.V143F in PCSK7 at frequency of 2/27,1/27 and 2/27 respectively. In vitro siRNA interference of UBE2O and PCSK7 resulted in down-regulated HAMP mRNA expression. Adenovirus generation of UBE2O p.K689R in cell lines resulted in increased expression of SMAD6 and SMAD7 and downregulation of p-SMAD1/5 and HAMP expression, and the reduction of hepcidin level. Conclusions Our study identified a series of novel candidate non-HFE mutations in Chinese patients with HH. These may provide insights into the genetic basis of unexplained primary iron overload.https://doi.org/10.1186/s13023-022-02349-yHereditary hemochromatosisNon-HFEUBE2OPCSK7Gene mutationIron overload |
| spellingShingle | Wei Zhang Yanmeng Li Anjian Xu Qin Ouyang Liyan Wu Donghu Zhou Lina Wu Bei Zhang Xinyan Zhao Yu Wang Xiaoming Wang Weijia Duan Qianyi Wang Hong You Jian Huang Xiaojuan Ou Jidong Jia China Registry of Genetic/Metabolic Liver Diseases (CR-GMLD) Group Identification of novel non-HFE mutations in Chinese patients with hereditary hemochromatosis Orphanet Journal of Rare Diseases Hereditary hemochromatosis Non-HFE UBE2O PCSK7 Gene mutation Iron overload |
| title | Identification of novel non-HFE mutations in Chinese patients with hereditary hemochromatosis |
| title_full | Identification of novel non-HFE mutations in Chinese patients with hereditary hemochromatosis |
| title_fullStr | Identification of novel non-HFE mutations in Chinese patients with hereditary hemochromatosis |
| title_full_unstemmed | Identification of novel non-HFE mutations in Chinese patients with hereditary hemochromatosis |
| title_short | Identification of novel non-HFE mutations in Chinese patients with hereditary hemochromatosis |
| title_sort | identification of novel non hfe mutations in chinese patients with hereditary hemochromatosis |
| topic | Hereditary hemochromatosis Non-HFE UBE2O PCSK7 Gene mutation Iron overload |
| url | https://doi.org/10.1186/s13023-022-02349-y |
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