A Novel Mutation of Transferrin Receptor 2 in a Chinese Pedigree With Type 3 Hemochromatosis: A Case Report

Tang, Shan; Bai, Li; Gao, Yuan; Hou, Weixin; Song, Wenyan; Liu, Hui; Hu, Zhongjie; Duan, Zhongping; Zhang, Liaoyun; Zheng, Sujun

doi:10.3389/fgene.2022.836431

Cited by 3 publications

(2 citation statements)

References 14 publications

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“…(Tyr320*); and SLC40A1 p. (Cys326Phe). [11][12][13][14] In a multi-center study, we have recently identified a series of variants in hemochromatosis in non-HFE genes, including HJV p.(His104Arg) and p.(Val274Met); TFR2 p.(Ala302Glu) and p.(Leu745Arg); and SLC40A1 p.(Tyr333His). 15,16 However, there are still many unexplained cases of primary iron overload with no causative variant in known hemochromatosis-related genes.…”

Section: Introductionmentioning

confidence: 99%

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SUGP2 p.(Arg639Gln) variant is involved in the pathogenesis of hemochromatosis via the CIRBP/BMPER signaling pathway

Li,

Xu,

Liu

et al. 2024

American J Hematol

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Pathogenic variants in HFE and non‐HFE genes have been identified in hemochromatosis in different patient populations, but there are still a certain number of patients with unexplained primary iron overload. We recently identified in Chinese patients a recurrent p.(Arg639Gln) variant in SURP and G‐patch domain containing 2 (SUGP2), a potential mRNA splicing‐related factor. However, the target gene of SUGP2 and affected iron‐regulating pathway remains unknown. We aimed to investigate the pathogenicity and underlying mechanism of this variant in hemochromatosis. RNA‐seq analysis revealed that SUGP2 knockdown caused abnormal alternative splicing of CIRBP pre‐mRNA, resulting in an increased normal splicing form of CIRBP V1, which in turn increased the expression of BMPER by enhancing its mRNA stability and translation. Furthermore, RNA‐protein pull‐down and RNA immunoprecipitation assays revealed that SUGP2 inhibited splicing of CIRBP pre‐mRNA by a splice site variant at CIRBP c.492 and was more susceptible to CIRBP c.492 C/C genotype. Cells transfected with SUGP2 p.(Arg639Gln) vector showed up‐regulation of CIRBP V1 and BMPER expression and down‐regulation of pSMAD1/5 and HAMP expression. CRISPR‐Cas9 mediated SUGP2 p.(Arg622Gln) knock‐in mice showed increased iron accumulation in the liver, higher total serum iron, and decreased serum hepcidin level. A total of 10 of 54 patients with hemochromatosis (18.5%) harbored the SUGP2 p.(Arg639Gln) variant and carried CIRBP c.492 C/C genotype, and had increased BMPER expression in the liver. Altogether, the SUGP2 p.(Arg639Gln) variant down‐regulates hepcidin expression through the SUGP2/CIRBP/BMPER axis, which may represent a novel pathogenic factor for hemochromatosis.

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Section: Introductionmentioning

confidence: 99%

“…(Gly430Arg) and p.(Gly430Arg)/p. (Tyr320*); and SLC40A1 p. (Cys326Phe) 11–14 . In a multi‐center study, we have recently identified a series of variants in hemochromatosis in non‐ HFE genes, including HJV p.(His104Arg) and p.(Val274Met); TFR2 p.(Ala302Glu) and p.(Leu745Arg); and SLC40A1 p.(Tyr333His) 15,16 .…”

Section: Introductionmentioning

confidence: 99%

SUGP2 p.(Arg639Gln) variant is involved in the pathogenesis of hemochromatosis via the CIRBP/BMPER signaling pathway

Li,

Xu,

Liu

et al. 2024

American J Hematol

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Novel mutation of transferrin receptor 2 causing hereditary hemochromatosis type 3 in a Japanese patient

Tamai,

Hosotani,

Shigefuku

et al. 2024

Hepatology Research

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Hereditary hemochromatosis (HH) is recognized as a progressive iron‐storage disorder, and leading to severe organ impairments, including liver cirrhosis. Hereditary hemochromatosis type 3 arises from mutations in the transferrin receptor 2 (TFR2) gene. However, HH type 3 is rare in Asia, and information regarding genetic mutations and associated phenotypes remains limited. Here, we reported the case of a Japanese patient with HH type 3, with a novel homozygous mutation of the TFR2 gene. A 69‐year‐old woman presented to our hospital with hand joint pain and was referred due to liver impairment. Viral hepatitis and autoimmune liver diseases were ruled out. However, the transferrin saturation was 92.2%, and the serum ferritin level was 1611.8 ng/mL. Additionally, abdominal computed tomography showed diffuse increased density of the liver parenchyma. Abdominal magnetic resonance imaging also suggested iron deposition. There is no history of prior treatments involving blood transfusions or iron agents. Her parents were involved in a consanguineous marriage, prompting genetic testing. She had a homozygous novel mutation, c.1337G>A (p.G446E), in the TFR2 gene. Serum hepcidin‐25 level was decreased to 2.9 ng/mL. According to the American Society of Medical Genetics and Genomics guideline, the mutation was classified as likely pathogenic, leading to the diagnosis of HH type 3. Following phlebotomy, her arthritis resolved, and serum transaminase levels were normalized. This case marks the first demonstration of homozygous mutation, c.1337G>A (p.G446E), in the TFR2 gene in patients with HH type 3.

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Case report: A rare case of hereditary hemochromatosis caused by a mutation in the HAMP gene in Fuyang, China

Wang,

Xu,

Jiang

et al. 2024

Front. Med.

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Hemochromatosis, also known as siderosis, is a disease caused by excessive iron deposition in human organs and tissues, resulting from iron metabolism disorders. It is clinically characterized by skin pigmentation (bronze color), liver cirrhosis, diabetes, weakness, and fatigue. Additional symptoms may include arthritis, hypothyroidism, heart failure, and sexual hypofunction. Clinical manifestations can vary from person to person, with a few patients showing no clinical manifestations, which makes the diagnosis difficult for clinicians. In this case report, we described hereditary hemochromatosis related to a mutation in the HAMP gene in Fuyang City, China, as a reference for clinicians. Hereditary hemochromatosis is rarely reported in China. Clinicians in China have relatively insufficient knowledge of this disease, which leads to frequent misdiagnosis. In this case report, we describe hereditary hemochromatosis related to HAMP gene mutation in Fuyang City, China, for the clinician’s reference.

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A Novel Mutation of Transferrin Receptor 2 in a Chinese Pedigree With Type 3 Hemochromatosis: A Case Report

Cited by 3 publications

References 14 publications

SUGP2 p.(Arg639Gln) variant is involved in the pathogenesis of hemochromatosis via the CIRBP/BMPER signaling pathway

SUGP2 p.(Arg639Gln) variant is involved in the pathogenesis of hemochromatosis via the CIRBP/BMPER signaling pathway

Novel mutation of transferrin receptor 2 causing hereditary hemochromatosis type 3 in a Japanese patient

Case report: A rare case of hereditary hemochromatosis caused by a mutation in the HAMP gene in Fuyang, China

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