Non- mutations in haemochromatosis in China: combination of heterozygous mutations involving signal peptide variants.

Tingxia Lv, Wei Zhang, Anjian Xu, Yanmeng Li, Donghu Zhou, Bei Zhang, Xiaojin Li, Xinyan Zhao, Yu Wang, Xiaoming Wang, Weijia Duan, Qianyi Wang, Hexiang Xu, JiShun Zheng, Rongrong Zhao, Longdong Zhu, Yuwei Dong, Lungen Lu, Yongpeng Chen, Jiang Long, Sujun Zheng, Wei Wang, Hong You, Jidong Jia, Xiaojuan Ou, Jian Huang

Journal: Journal of medical genetics 2019;55(10):650-660

PMID: 30166352

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Abstract

INTRODUCTION

Hereditary haemochromatosis (HH) caused by a homozygous p.C282Y mutation in haemochromatosis () gene has been well documented. However, less is known about the causative non- mutation. We aimed to assess mutation patterns of haemochromatosis-related genes in Chinese patients with primary iron overload.

METHODS

Patients were preanalysed for mutations in the classic HH-related genes: , , , and . Whole exome sequencing was conducted for cases with variants in signal peptide region. Representative variants were analysed for biological function.

RESULTS

None of the cases analysed harboured the p.C282Y; however, 21 of 22 primary iron-overload cases harboured at least one non-synonymous variant in the non- genes. Specifically, p.E3D or p.Q6H variants in the signal peptide region were identified in nine cases (40.9%). In two of three probands with the p.E3D, exome sequencing identified accompanying variants in BMP/SMAD pathway genes, including p.T331M and p.R269Q, and interestingly, p.R639Q was identified in all the three cases. Pedigree analysis showed a similar pattern of combination of heterozygous mutations in cases with p.E3D or p.Q6H, with p.R639Q or p.C321X being common mutation. In vitro siRNA interference of showed a novel role of downregulating the BMP/SMAD pathway. Site-directed mutagenesis of p.Q6H/p.C321X in cell lines resulted in loss of membrane localisation of mutant HJV, and downregulation of p-SMAD1/5 and .

CONCLUSION

Compound heterozygous mutations of or combined heterozygous mutations of BMP/SMAD pathway genes, marked by variants in the signal peptide region, may represent a novel aetiological factor for HH.

Address: Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China.; Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China.; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China.; Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China.; Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Clinical Research Center for Rare Liver Disease, Capital Medical University, Beijing, China.; Liver Research Center, National Clinical Research Center for Digestive Diseases, Beijing, China.; Department of Infectious Diseases, The Third Affiliated Hospital of Anhui Medical University, The First People's Hospital of Hefei, Hefei, China.; Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, China.; Department of Gastroenterology, School of Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.; Department of Infectious Diseases, Institute of Hepatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.; Department of Oncology Minimally Invasive Interventional Radiology, Beijing You-An Hospital, Capital Medical University, Shanghai, China.; Artificial Liver Center, Beijing You-An Hospital, Capital Medical University, Beijing, China.; Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

DOI: 10.1136/jmedgenet-2018-105348

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MeSH Terms: Adolescent, Adult, Aged, China, Cohort Studies, Female, GPI-Linked Proteins, Genetic Variation, Hemochromatosis, Hemochromatosis Protein, Heterozygote, Humans, Iron Overload, Male, Middle Aged, Mutation, Protein Sorting Signals, Smad Proteins, Exome Sequencing, Young Adult