Non-<i>HFE</i> mutations in haemochromatosis in China: combination of heterozygous mutations involving <i>HJV</i> signal peptide variants

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

doi:10.1136/jmedgenet-2018-105348

Cited by 25 publications

(49 citation statements)

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“…Furthermore, HFE p.C282Y mutation had been identified neither in a variety of disorders in China such as chronic hepatitis C, nonalcoholic fatty liver disease (Lin et al, 2005), cardiovascular disease (Bi et al, 2013), myelodysplastic syndromes, and aplastic anemia (Nie et al, 2010), nor in general population (Lin et al, 2007). In addition, we recently analyzed 22 patients with primary iron overload and no HFE variants were identified (Lv et al, 2018). Therefore, although very rare, HFE gene mutations should not be ignored as a possible cause of hemochromatosis in Asians.…”

Section: Discussionmentioning

confidence: 99%

“…Genomic DNA was extracted from peripheral blood leukocytes using the Genomic DNA Purification Kit (Qiagen, Valencia, CA). All exons of HFE, HJV, HAMP, TFR2, and SLC40A1 were PCR amplified with their associated boundary regions using the primers described in our previous study (Lv et al, 2018). PCR products were sequenced in forward and reverse orientations using an automated ABI3730 DNA sequencer (ABI).…”

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HFE-Related Hemochromatosis in a Chinese Patient: The First Reported Case

et al. 2020

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HFE-Related Hemochromatosis in a Chinese Patient: The First Reported Case

et al. 2020

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“…In the current pedigree analysis, we found only eight patients with a homozygous mutation, and most of the patients (43/65) harbored two or more heterozygous mutations on different alleles. Coordinately, recent studies have shown that compound heterozygous mutations of disease‐causing gene may represent another type of mutation pattern in addition to homozygous mutations in autosomal inherited diseases (Lv et al, ). Interestingly, we also found single heterozygous mutations in as many as 12 confirmed cases, as well as two heterozygous mutations on one allele (1/65); these results are inconsistent with the features of a recessive genetic disease.…”

Section: Discussionmentioning

confidence: 99%

Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants

Zhang

Zhou

et al. 2019

Human Mutation

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Wilson disease (WD) is a rare autosomal recessive genetic disorder that is associated with various mutations in the ATP7B gene. Although ATP7B variants are frequently identified, the exact mutation patterns remain unknown because of the absence of pedigree studies, and the functional consequences of individual ATP7B variants remain to be clarified. In this study, we recruited 65 clinically diagnosed WD patients from 60 unrelated families. Pedigree analysis showed that besides several ATP7B homozygous variants (8/65, 12.3%), compound heterozygous variants (43/65, 66.2%) were present in the majority of WD patients. There were 20% of the patients had one (12/65, 18.5%) or multiple (1/65, 1.5%) variants in only a single allele, characterized by a high ratio of splicing or frameshift variants. Nine ATP7B variants were cloned into the pAG426GPD yeast expression vector to evaluate their functional consequences, and the results suggested different degrees of functional disruption from mild or uncertain to severe, consistent with the corresponding phenotypes. Our study revealed the complex ATP7B mutation patterns in WD patients and the applicability of a yeast model system to the Human Mutation. 2019;40:552-565. wileyonlinelibrary.com/journal/humu 552 |

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“…Although the majority of these are reported as pathogenic, there may be some doubt in cases that lacked phenotypic, segregation or functional data . SLC40A1 mutations have been reported in Chinese haemochromatosis patients, including missense mutations W158C and S209L, small deletions mutation V162del and splicing variants IVS 3+10 del gtt and IVS1‐8C/G …”

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confidence: 99%

A novel SLC40A1 p.Y333H mutation with gain of function of ferroportin: A recurrent cause of haemochromatosis in China

Zhang

et al. 2018

Liver International

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Background & Aims:Haemochromatosis type 4, also known as ferroportin disease, is an autosomal dominant genetic disorder caused by pathogenic mutations in the SLC40A1 gene, which encodes ferroportin 1 (FPN1). We have identified a novel SLC40A1 p.Y333H mutation in our previous study. In the present study, we tried to investigate the frequency and pathogenicity of the SLC40A1 p.Y333H mutation in haemochromatosis in China. Methods:Patients were analysed for SLC40A1 p.Y333H as well as mutations in the other classic haemochromatosis-related genes by Sanger sequencing. To analyse iron export capacity of the SLC40A1 p.Y333H mutant, the 293T cells were transfected with the SLC40A1 p.Y333H construct and then treated with hepcidin after exposure to ferric ammonium citrate. Cellular localization of mutant FPN1, expression of FPN1 and intracellular ferritin were analysed by immunofluorescence and Western blotting.Results: Of 22 unrelated cases with primary iron overload, three cases (3/22, 13.6%) harboured the SLC40A1 p.Y333H, with no missense mutations identified in any other classical haemochromatosis-related genes including HFE, HJV, HAMP and TFR2.Pedigree analysis showed that three probands and the son of one proband had haemochromatosis of stage 3, while the son of another proband with age of 16 showed elevated transferrin saturation but normal serum ferritin level. In vitro studies showed the mutant p.Y333H ferroportin was resistant to hepcidin, affecting the See Editorial on page 1014 | 1121 ZHANG et Al.

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

Abstract: 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.

Cited by 25 publications

References 48 publications

HFE-Related Hemochromatosis in a Chinese Patient: The First Reported Case

HFE-Related Hemochromatosis in a Chinese Patient: The First Reported Case

Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants

A novel SLC40A1 p.Y333H mutation with gain of function of ferroportin: A recurrent cause of haemochromatosis in China

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