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Published on: February 24, 2014
Identification of novel non-HFE mutations in Chinese patients with hereditary hemochromatosis
Wei Zhang1,2, Yanmeng Li2,3, Anjian Xu2,3
1Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, 95 Yong-An Road, Beijing, 100050, China.
Insights
Researchers identified novel non-HFE gene mutations in Chinese patients with hereditary hemochromatosis (HH). These findings offer new insights into the genetic causes of primary iron overload in this population.
Area of Science:
- Genetics
- Molecular Biology
- Human Physiology
Background:
- Hereditary hemochromatosis (HH) is primarily linked to HFE gene mutations in Caucasians.
- Non-HFE mutations are a significant cause of HH in Chinese populations.
- A notable proportion of primary iron overload cases in Chinese patients remain unexplained by known mutations.
Purpose of the Study:
- To investigate novel non-HFE gene mutations in Chinese individuals with unexplained primary iron overload.
- To identify new genetic factors contributing to hereditary hemochromatosis in the Chinese population.
Main Methods:
- Whole exome sequencing was performed on 9 cases with unexplained primary iron overload.
- Candidate genes were further screened in an additional 18 HH cases using Sanger sequencing.
- In vitro functional analyses were conducted on selected genes and variants.
Main Results:
- Whole exome sequencing identified 42 missense variants in 40 iron metabolism-related genes.
- Mutations in UBE2O (p.K689R) and PCSK7 (p.R711W, p.V143F) were identified in Chinese HH patients.
- In vitro studies showed UBE2O and PCSK7 influence HAMP (hepcidin) expression, a key regulator of iron homeostasis.
Conclusions:
- Novel candidate non-HFE mutations were identified in Chinese HH patients.
- These findings contribute to understanding the genetic basis of unexplained primary iron overload.
- The study highlights the genetic heterogeneity of hereditary hemochromatosis in diverse populations.
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.
