GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes

Barton, James C.; Chen, Wen-Pin; Emond, Mary J.; Phatak, Pradyumna D.; Subramaniam, V. Nathan; Adams, Paul C.; Gurrin, Lyle C.; Anderson, Gregory J.; Ramm, Grant A.; Powell, Lawrie W.; Allen, Katrina J.; Phillips, John D.; Parker, Charles J.; McLaren, Gordon D.; McLaren, Christine E.

doi:10.1016/j.bcmd.2016.11.009

Cited by 13 publications

(7 citation statements)

References 38 publications

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“…There were no differences in HIC, SIC or relative mRNA levels of Hamp in the livers of the 10-and 26-week-old male mice (Figures 2 and 3). These results suggest that reduced Gnpat expression may not affect Hfe knockout mice in contrast with what might have expected from the patient studies, where the GNPAT p.D519G polymorphism was associated with more severe iron overload in HFE hemochromatosis patients [17].…”

Section: Gnpat +/− Heterozygosity Does Not Affect Iron Homeostasis Incontrasting

confidence: 55%

“…GNPAT has been suggested to act as a genetic modifier of HH in patients with mutations in HFE [ 14 , 16 , 17 ]. Other reports using different cohorts failed to identify this similar correlation between HFE and GNPAT in patients with HH [ 18–20 ].…”

Section: Discussionmentioning

confidence: 99%

“…The GNPAT p.D519G variant has been identified as a cause of the peroxisomal disorder rhizomelic chondrodysplasia punctata (RCDP) 2 [ 15 ], where it was shown to lead to a 70% decrease in enzymatic activity of GNPAT [ 15 ]. Subsequently, a number of studies either supporting [ 16 , 17 ] or opposing [ 18–20 ] the role of GNPAT as a modifier of HFE hemochromatosis have been reported. Interestingly, it was also reported that in response to an oral iron tolerance test, subjects with GNPAT polymorphisms had significantly higher serum iron levels, transferrin saturation [ 21 , 22 ] and loaded more iron compared with subjects who did not have this polymorphism, even in the absence of the HFE mutations.…”

Section: Introductionmentioning

confidence: 99%

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Dysregulated hepcidin response to dietary iron in male mice with reduced Gnpat expression

et al. 2020

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Exome sequencing has identified the glyceronephosphate O-acyltransferase (GNPAT) gene as a genetic modifier of iron overload in hereditary hemochromatosis. Subjects with HFE (Homeostatic Iron Regulator) p.C282Y mutations and the GNPAT p.D519G variant had more iron loading compared to subjects without the GNPAT variant. In response to an oral iron challenge, women with GNPAT polymorphisms loaded more iron as compared to women without polymorphisms, reinforcing a role for GNPAT in iron homeostasis. The aim of this study was to develop and characterize an animal model of disease to further our understanding of genetic modifiers, and in particular, the role of GNPAT in iron homeostasis. We generated a Hfe/Gnpat mouse model reminiscent of the patients previously studied and studied these mice for up to 26 weeks. We also examined the effect of dietary iron loading on mice with reduced Gnpat expression. Gnpat heterozygosity in Hfe knockout mice does not play a role in systemic iron homeostasis; Gnpat+/- mice fed a high-iron diet, however, had lower hepatic hepcidin mRNA expression, whereas they have significantly higher serum iron levels and transferrin saturation compared to wildtype littermates on a similar diet. These results reinforce an independent role of GNPAT in systemic iron homeostasis, reproducing in an animal model the observations in women with GNPAT polymorphisms subjected to an iron tolerance test.

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Section: Gnpat +/− Heterozygosity Does Not Affect Iron Homeostasis Incontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dysregulated hepcidin response to dietary iron in male mice with reduced Gnpat expression

et al. 2020

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“…HFE is a membrane protein that heterodimerizes with β2-microglobulin [ 33 ]. C282Y mutation disrupts a disulfide bond in the α3 domain of HFE ; it abrogates its binding to β2-microglobulin and, consequently, prevents HFE presentation on the cell surface [ 34 ]. Although identification of HFE mutation(s) was a milestone in early diagnosis of hemochromatosis, at the time when the C282Y mutation has been identified (1996) [ 35 ], the mechanisms through which mutated HFE causes systemic iron overload and the role in the upregulation of intestinal absorption of dietary iron was unclear.…”

Section: Resultsmentioning

confidence: 99%

Pathogenesis, Diagnosis, and Clinical Implications of Hereditary Hemochromatosis—The Cardiological Point of View

Daniłowicz‐Szymanowicz

Sikorska

Starzyński

et al. 2021

Diagnostics

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Hereditary hemochromatosis (HH) is a genetic disease leading to excessive iron absorption, its accumulation, and oxidative stress induction causing different organ damage, including the heart. The process of cardiac involvement is slow and lasts for years. Cardiac pathology manifests as an impaired diastolic function and cardiac hypertrophy at first and as dilatative cardiomyopathy and heart failure with time. From the moment of heart failure appearance, the prognosis is poor. Therefore, it is crucial to prevent those lesions by upfront therapy at the preclinical phase of the disease. The most useful diagnostic tool for detecting cardiac involvement is echocardiography. However, during an early phase of the disease, when patients do not present severe abnormalities in serum iron parameters and severe symptoms of other organ involvement, heart damage may be overlooked due to the lack of evident signs of cardiac dysfunction. Considerable advancement in echocardiography, with particular attention to speckle tracking echocardiography, allows detecting discrete myocardial abnormalities and planning strategy for further clinical management before the occurrence of substantial heart damage. The review aims to present the current state of knowledge concerning cardiac involvement in HH. In addition, it could help cardiologists and other physicians in their everyday practice with HH patients.

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“…Supported by studies in the HFE-HH animal model, efforts have been made to identify genetic modifiers in humans [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 25 ]. Several polymorphic variants in genes involved in iron metabolism or even apparently unrelated (e.g., PCSK7 , GNPAT ) have been proposed as potential modifiers of HFE-HH phenotype, although results have often been controversial [ 9 , 26 ]. However, there might be several reasons to explain these differences.…”

Section: Discussionmentioning

confidence: 99%

HIF1A: A Putative Modifier of Hemochromatosis

Pelucchi

Ravasi

Arosio³

et al. 2021

IJMS

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HFE-related hereditary hemochromatosis (HH) is characterized by marked phenotypic heterogeneity. Homozygosity for p.C282Y is a low penetrance genotype suggesting that the HFE-HH is a multifactorial disease resulting from a complex interaction involving a major gene defect, genetic background and environmental factors. We performed a targeted NGS-based gene panel to identify new candidate modifiers by using an extreme phenotype sampling study based on serum ferritin and iron removed/age ratio. We found an increased prevalence of the HIF1A p.Phe582Ser and p.Ala588Thr variants in patients with a severe iron and clinical phenotype. Accordingly, Huh-7 cells transfected with both variants showed significantly lower HAMP promoter activity by luciferase assay. The qRT-PCR assays showed a downregulation of hepcidin and an upregulation of the HIF1A target genes (VEGF, HMOX, FUR, TMPRSS6) in cells transfected with the HIF1A-P582S vector. We identified mutations in other genes (e.g., Serpina1) that might have some relevance in single cases in aggravating or mitigating disease manifestation. In conclusion, the present study identified HIF1A as a possible modifier of the HFE-HH phenotype cooperating with the genetic defect in downregulating hepcidin synthesis. In addition, this study highlights that an NGS-based approach could broaden our knowledge and help in characterizing the genetic complexity of HFE-HH patients with a severe phenotype expression.

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GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes

Cited by 13 publications

References 38 publications

Dysregulated hepcidin response to dietary iron in male mice with reduced Gnpat expression

Dysregulated hepcidin response to dietary iron in male mice with reduced Gnpat expression

Pathogenesis, Diagnosis, and Clinical Implications of Hereditary Hemochromatosis—The Cardiological Point of View

HIF1A: A Putative Modifier of Hemochromatosis

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