Genetic causes of erythrocytosis and the oxygen-sensing pathway

Lee, Frank S.

doi:10.1016/j.blre.2008.04.003

Cited by 40 publications

(43 citation statements)

References 94 publications

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“…This in turn suggests that impairment of the PHD2/HIF-2␣ interaction alone is sufficient to induce erythrocytosis, and is consistent with the fact that mutations in PHD2 alone comprise a distinct cause of erythrocytosis (10,12,14,30,31). That impairment of the HIF-␣/VHL interaction alone is sufficient to induce erythrocytosis is independently supported by the existence of erythrocytosis-associated VHL mutations (10,13,20,(32)(33)(34).…”

Section: Discussionsupporting

confidence: 54%

Erythrocytosis-associated HIF-2α Mutations Demonstrate a Critical Role for Residues C-terminal to the Hydroxylacceptor Proline

Furlow

Percy

Sutherland

et al. 2009

Journal of Biological Chemistry

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A classic physiologic response to hypoxia in humans is the up-regulation of the ERYTHROPOIETIN (EPO) gene, which is the central regulator of red blood cell mass. The EPO gene, in turn, is activated by hypoxia inducible factor (HIF). HIF is a transcription factor consisting of an ␣ subunit (HIF-␣) and a ␤ subunit (HIF-␤). Under normoxic conditions, prolyl hydroxylase domain protein (PHD, also known as HIF prolyl hydroxylase and egg laying-defective nine protein) site specifically hydroxylates HIF-␣ in a conserved LXXLAP motif (where underlining indicates the hydroxylacceptor proline). This provides a recognition motif for the von Hippel Lindau protein, a component of an E3 ubiquitin ligase complex that targets hydroxylated HIF-␣ for degradation. Under hypoxic conditions, this inherently oxygen-dependent modification is arrested, thereby stabilizing HIF-␣ and allowing it to activate the EPO gene. We previously identified and characterized an erythrocytosis-associated HIF2A mutation, G537W. More recently, we reported two additional erythrocytosis-associated HIF2A mutations, G537R and M535V. Here, we describe the functional characterization of these two mutants as well as a third novel erythrocytosisassociated mutation, P534L. These mutations affect residues C-terminal to the LXXLAP motif. We find that all result in impaired degradation and thus aberrant stabilization of HIF-2␣. However, each exhibits a distinct profile with respect to their effects on PHD2 binding and von Hippel Lindau interaction. These findings reinforce the importance of HIF-2␣ in human EPO regulation, demonstrate heterogeneity of functional defects arising from these mutations, and point to a critical role for residues C-terminal to the LXXLAP motif in HIF-␣.

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Section: Discussionsupporting

confidence: 54%

Erythrocytosis-associated HIF-2α Mutations Demonstrate a Critical Role for Residues C-terminal to the Hydroxylacceptor Proline

Furlow

Percy

Sutherland

et al. 2009

Journal of Biological Chemistry

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“…The decrease of oxygen transport capacity results in tissue hypoxia in different organs and subsequently leads to arteriospasm (10). Chronic hypoxia is responsible for compensatory erythrocytosis, resulting in increasing blood viscosity and decreasing tissue perfusion (11). These factors are detrimental for the healing of diabetic foot ulcers, which may increase the risk of diabetic foot amputation.…”

Section: Introductionmentioning

confidence: 99%

Smoking increases the risk of diabetic foot amputation: A meta-analysis

et al. 2017

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Abstract. Accumulating evidence suggests that smoking is associated with diabetic foot amputation. However, the currently available results are inconsistent and controversial. Therefore, the present study performed a meta-analysis to systematically review the association between smoking and diabetic foot amputation and to investigate the risk factors of diabetic foot amputation. Public databases, including PubMed and Embase, were searched prior to 29th February 2016. The heterogeneity was assessed using the Cochran's Q statistic and the I 2 statistic, and odds ratio (OR) and 95% confidence interval (CI) were calculated and pooled appropriately. Sensitivity analysis was performed to evaluate the stability of the results. In addition, Egger's test was applied to assess any potential publication bias. Based on the research, a total of eight studies, including five cohort studies and three case control studies were included. The data indicated that smoking significantly increased the risk of diabetic foot amputation (OR=1.65; 95% CI, 1.09-2.50; P<0.0001) compared with non-smoking. Sensitivity analysis demonstrated that the pooled analysis did not vary substantially following the exclusion of any one study. Additionally, there was no evidence of publication bias (Egger's test, t=0.1378; P=0.8958). Furthermore, no significant difference was observed between the minor and major amputation groups in patients who smoked (OR=0.79; 95% CI, 0.24-2.58). The results of the present meta-analysis suggested that smoking is a notable risk factor for diabetic foot amputation. Smoking cessation appears to reduce the risk of diabetic foot amputation.

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“…While EGLN1/PHD2 and EPAS1/HIF2A regulate various aspects of tissue and cellular homeostasis, the PHD/ VHL/HIF axis is directly involved in erythropoiesis (Lee 2008;Furlow et al 2009). It is unclear whether coordinated signaling mediated by these adaptive HIF pathway members directly or indirectly affects Hb level (Storz et al 2010;Beall 2011), as the precise variants and their functions remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

Genetic determinants of Tibetan high-altitude adaptation

et al. 2011

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Some highland populations have genetic adaptations that enable their successful existence in a hypoxic environment. Tibetans are protected against many of the harmful responses exhibited by non-adapted populations upon exposure to severe hypoxia, including elevated hemoglobin concentration (i.e., polycythemia). Recent studies have highlighted several genes subject to natural selection in native high-altitude Tibetans. Three of these genes, EPAS1, EGLN1 and PPARA, regulate or are regulated by hypoxia inducible factor, a principal controller of erythropoiesis and other organismal functions. Uncovering the molecular basis of hypoxic adaptation should have implications for understanding hematological and other adaptations involved in hypoxia tolerance. Because the hypoxia response involves a variety of cardiovascular, pulmonary and metabolic functions, this knowledge would improve our understanding of disease mechanisms and could ultimately be translated into targeted therapies for oxygen deprivation, cardiopulmonary and cerebral pathologies, and metabolic disorders such as diabetes and obesity.

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Genetic causes of erythrocytosis and the oxygen-sensing pathway

Cited by 40 publications

References 94 publications

Erythrocytosis-associated HIF-2α Mutations Demonstrate a Critical Role for Residues C-terminal to the Hydroxylacceptor Proline

Erythrocytosis-associated HIF-2α Mutations Demonstrate a Critical Role for Residues C-terminal to the Hydroxylacceptor Proline

Smoking increases the risk of diabetic foot amputation: A meta-analysis

Genetic determinants of Tibetan high-altitude adaptation

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