DENND3 p.L708V activating variant is involved in the pathogenesis of hereditary hemochromatosis via the RAB12/TFR2 signaling pathway

Li, Yanmeng; Xu, Anjian; Ouyang, Qing; Zhang, Wei; Zhang, Chunpan; Chen, Zhibin; Zhou, Donghu; Zhang, Bei; Duan, Weijia; Zhao, Xinyan; Wang, Xiaoming; You, Hong; Ou, Xiaojuan; Jia, Ji-dong; Huang, Jian

doi:10.1007/s12072-022-10474-w

Cited by 3 publications

(9 citation statements)

References 29 publications

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“…Patients with primary iron overload were enrolled at the China Registry of Genetic/Metabolic Liver Diseases (CR‐GMLD, Clinicaltrials.gov: NCT03131427) for the genetic analysis of variants in the SUGP2 gene. Among the enrolled patients, 31 showed variants in hemochromatosis‐related genes, 17 and an additional 23 hemochromatosis patients were shown in Table S1. Hemochromatosis was diagnosed based on the American Association for the Study of Liver Diseases 2011 practice guidelines on hemochromatosis 24 .…”

Section: Methodsmentioning

confidence: 99%

“…Sanger sequencing was conducted as described previously 17 . All exons of SUGP2 were PCR‐amplified with SUGP2‐associated boundary regions using primers designed with Primer 6 software (Table S2).…”

Section: Methodsmentioning

confidence: 99%

“…For the identification of accompanied variation in other iron metabolic related genes in patients with SUGP2 p.(Arg639Gln) in heterozygosity, exome sequencing was conducted as described previously 17 …”

Section: Methodsmentioning

confidence: 99%

“…Sanger sequencing was conducted as described previously. 17 All exons of SUGP2 were PCR-amplified with SUGP2-associated boundary regions using primers designed with Primer 6 software (Table S2). In addition, primers were designed also for PCR amplification of the gene sequence between CIRBP (NM_001280) exon 6 to 7 (Table S2).…”

Section: Sanger Sequencing For Sugp2 Gene and Cirbp C492t>c Variantmentioning

confidence: 99%

“…However, there are still many unexplained cases of primary iron overload with no causative variant in known hemochromatosis‐related genes. By whole exome sequencing, we have identified novel genetic variants in genes involved in iron metabolism, 7,15,17 including in SURP and G‐patch domain containing 2 ( SUGP2 ), a known splicing‐related factor. The recurrent SUGP2 p.(Arg639Gln) variant (NM_001017392.5) was observed in patients with primary iron overload in our follow‐up study 15 …”

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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Sanger Sequencing For Sugp2 Gene and Cirbp C492t>c Variantmentioning

confidence: 99%

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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Identification of lysosome-related hub genes as potential biomarkers and immune infiltrations of moyamoya disease by multiple bioinformatics methods and machine-learning strategies

Li,

Zhao,

et al. 2024

Heliyon

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Recurrent BMP4 variants in exon 4 cause non-HFE-associated hemochromatosis via the BMP/SMAD signaling pathway

Ouyang,

Li,

et al. 2024

Orphanet J Rare Dis

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Background Hereditary hemochromatosis (HH) is an iron overload disorder and can be caused by variants in non-HFE genes in Chinese patients. However, there is still a considerable proportion of patients suffering from unexplained iron overload. In our previous study, we had identified the p.R269Q variant in exon 4 of the Bone morphogenetic protein 4 (BMP4) gene in Chinese patients with unexplained primary iron overload by Whole Exome sequencing, and then the BMP4 p.H251Y variant was identified by Sanger sequencing in a Chinese patient with secondary iron overload. Our study aimed to explore the pathogenicity and underlying mechanism of BMP4 p.H251Y and BMP4 p.R269Q variants in patients with iron overload. Methods Sanger sequencing was conducted to identify the novel variants in the BMP4 gene of patients with unexplained iron overload. MRI and liver biopsy were used to display iron overload in the liver of the patient harboring the BMP4 p.H251Y variant. The BMP4 and hepcidin levels in BMP4 knockdown and BMP4 variant cells were examined by enzyme-linked immunosorbent assay. The effects of BMP4 p.H251Y and BMP4 p.R269Q variants on the hepcidin-regulation pathway were studied. Results One of 54 HH patients (1.85%) harbored the BMP4 p.R269Q variant. One of 148 patients (0.68%) with secondary hemochromatosis harbored the BMP4 p.H251Y variant, and these two variants were not found in 100 Chinese general population. For the patient harboring the BMP4 p.H251Y variant, abdominal MRI and Perl's staining of liver tissue displayed iron overload in the liver. Cells transfected with the BMP4 p.H251Y and p.R269Q variants showed down-regulation of hepcidin level and BMP/SMAD pathway compared with cells transfected with the wild-type BMP4 vector. Conclusion The BMP4 p.H251Y and p.R269Q variants can downregulate hepcidin levels by inhibiting the BMP/SMAD axis, suggesting they may play pathogenic roles in iron overload.

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DENND3 p.L708V activating variant is involved in the pathogenesis of hereditary hemochromatosis via the RAB12/TFR2 signaling pathway

Cited by 3 publications

References 29 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

Identification of lysosome-related hub genes as potential biomarkers and immune infiltrations of moyamoya disease by multiple bioinformatics methods and machine-learning strategies

Recurrent BMP4 variants in exon 4 cause non-HFE-associated hemochromatosis via the BMP/SMAD signaling pathway

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