Genetic variability of hypoxia‐inducible factor alpha (HIFA) genes in familial erythrocytosis: Analysis of the literature and genome databases

Abstract

Familial erythrocytosis (FE) is a congenital disorder, defined by elevated red blood cell number, hemoglobin, and hematocrit. Among eight types of FE, type 4 is caused by variants in the EPAS1 gene. Two other hypoxia‐inducible factor alpha (HIFA) subunits, HIF1A and HIF3A, have not yet been associated with medical history of FE, but have potential role in the development of erythrocytosis. To improve diagnosis, it is crucial to identify new variants in genes involved in erythrocyte production. Published literature and data from genome browsers were used to obtain HIFA sequence variants associated with erythrocytosis and to locate them on protein sequence and regulatory sites. We retrieved 24 variants from the literature: 2 in HIF1A, 20 in EPAS1 and 2 in HIF3A gene. Sixteen out of 20 variants in the EPAS1 gene are positioned in a conserved region of 13 amino acids within exon 12, next to regulatory post‐translational modification and binding sites, suggesting that EPAS1 has an important role in erythropoiesis. The role of HIF1A and HIF3A in the development of erythrocytosis should be further investigated.

A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin

“…The data presented in this study may provide basis for human disease. Two single-nucleotide variants in the HIF3A locus have been associated with familial erythrocytosis [42]. The data reported here suggest that it may be through a direct transactivation effect.…”

Exposure to hypoxia causes stress erythropoiesis and downregulates immune response genes in spleen of mice

“…However, only Hif3α , involved in the regulation of EPO signaling [ 61 ], was upregulated in our data. Two variants of the HIF3A gene were associated with familial erythrocytosis in human [ 62 ]. During the hypoxic condition, stabilized HIF-α activates transcription of target genes with Arnt (HIF-1β) in the nucleus [ 63 ].…”

Genetic analysis of 39 erythrocytosis and hereditary hemochromatosis‐associated genes in the Slovenian family with idiopathic erythrocytosis

“…Secondary congenital erythrocytosis is classified into remaining seven types (ECYT2-8), and these are caused by variants in genes involved in the oxygen-sensing pathway (VHL, EGLN1, EPAS1, EPO) or variants that affect the haemoglobin oxygen affinity (HBB, HBA1, HBA2, BPGM) (Table 1). [6][7][8][9] Oxygen homeostasis is The majority of the variants associated with ECYT1-8 have been collected in the Global Variome shared Leiden Open Variation Database (LOVD), which is supported by the LOVD 3.x software. 11 Along with the nine genes responsible for ECYT1-8, other key genes are involved in the erythropoiesis pathway and are hence plausible target genes for the development of erythrocytosis.…”

“…Secondary congenital erythrocytosis is classified into remaining seven types (ECYT2‐8), and these are caused by variants in genes involved in the oxygen‐sensing pathway ( VHL , EGLN1 , EPAS1 , EPO ) or variants that affect the haemoglobin oxygen affinity ( HBB , HBA1 , HBA2 , BPGM ) (Table 1). 6‐9 Oxygen homeostasis is regulated through a complex pathway that is mediated by the essential transcription factors known as hypoxia‐inducible factors (HIFs). HIFs can up‐regulate a number of target genes involved in maintenance of sufficient tissue oxygenation, including the hormone EPO, which regulates proliferation and differentiation of erythroid progenitors.…”