Elucidating loss-of-function mechanisms of monoallelic EPAS1 mutations underlying congenital hypoplastic anaemia in a paediatric anaemia cohort
Jiasheng Zhang and Jin Sun contributed equally to this work.
Summary
HIF-2α, encoded by EPAS1, plays a dominant role in regulating erythropoietin (EPO) production, maintaining the dynamic balance of erythropoiesis. Gain-of-function mutations in EPAS1 cause erythrocytosis. However, anaemia caused by EPAS1 loss-of-function mutations has been confined to only one case report, and the underlying mechanism remains unclear. Herein, the reanalysis of high-throughput sequencing data from 311 patients with anaemia identified three monoallelic EPAS1 variants from three unrelated families in a paediatric anaemia cohort. The probands showed highly consistent clinical phenotypes with normocytic and normochromic anaemia, reticulocytopenia and relative deficiency of serum EPO, characterised as congenital hypoplastic anaemia. In vitro studies suggested that defects in steady-state protein abundance, nuclear localisation and binding with co-activator in EPAS1 variants lead to impaired EPO transcriptional activation. Therefore, loss-of-function mutations in EPAS1 can cause erythroid hypoplasia in an EPO-dependent manner. This study identified a new causative gene for congenital hypoplastic anaemia and clarified the molecular aetiology of loss-of-function EPAS1 mutations.
Graphical Abstract
HIF-2α, encoded by EPAS1, is the main transcriptional factor of EPO production in the kidney, which maintains the dynamic balance of erythropoiesis. Herein, three monoallelic EPAS1 variants from three unrelated families were identified in a paediatric anaemia cohort. Highly consistent clinical phenotypes with normocytic and normochromic anaemia, reticulocytopenia and relative deficiency of serum EPO were revealed in the patients. The HIF-2α mutants showed defects in steady-state protein abundance, nuclear localisation and binding with co-activator, which lead to impaired EPO transcriptional activation. These findings indicated monoallelic EPAS1 variants cause congenital hypoplastic anaemia depending on EPO production in a loss-of-function mechanism.
CONFLICT OF INTEREST STATEMENT
The authors declare no competing interests.
Open Research
DATA AVAILABILITY STATEMENT
Supplementary material associated with this article can be found in the online version.
