# Role of VPS4A and ESCRT-III in terminal erythropoiesis

> **NIH NIH K01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $151,513

## Abstract

Project Summary
Congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of genetic disorders characterized by
ineffective erythropoiesis, hemolysis, and bi- or multi-nucleated erythroblasts in the bone marrow. The
mechanisms of erythroid dysfunction in CDAs are incompletely understood; studying the molecular defects in
these diseases can reveal critical pathways in terminal erythropoiesis. We have identified mutations in VPS4A
as a novel cause of CDA in three unrelated patients with a syndrome of dyserythropoiesis, hemolytic anemia,
and neurodevelopmental delay, pointing to the importance of Vacuolar Protein Sorting 4A (VPS4A) for terminal
erythropoiesis and normal red blood cell survival. However, the mechanisms of its action need further
investigation. VPS4A is an ATPase that has been shown in yeast and in vitro cell cultures to participate with the
Endosomal Sorting Complex Required for Transport (ESCRT)-III in endosomal vesicle trafficking, viral budding,
and the abscission step of cytokinesis. It is required for budding of endosomal vesicles into multivesicular bodies,
a critical step in the pathway for the sorting, recycling, and removal of transmembrane protein receptors. We
have shown for the first time a human disease in patients with dominant negative mutations in the ATPase
domain of VPS4A, resulting in dyserythropoiesis with erythroblasts connected by cytoplasmic bridges consistent
with cytokinesis failure at the abscission step and reticulocytes with evidence of altered trafficking of the
transferrin receptor (TfR1/CD71). We hypothesize that VPS4A is essential for terminal erythropoiesis and that
loss of function results in dyserythropoiesis through a combination of cytokinesis failure and endolysosomal
defects. The goal of this work is to define the molecular mechanisms by which these VPS4A variants disturb
erythropoiesis, and to elucidate the roles of VPS4A and the ESCRT machinery in human and murine terminal
erythropoiesis. We aim to model the erythroid defects due to VPS4 in vivo using a transgenic mouse model with
erythroid-targeted expression of a known dominant-negative VPS4 mutant (VPS4EQ), enabling studies on the
pathogenic mechanisms and natural history of the disease (Aim 1). Using human iPSCs, we will investigate the
contributions of cytokinesis failure and iron trafficking defects to the dyserythropoiesis observed in these
individuals using normal, patient-derived, and VPS4AEQ CRISPR gene-edited iPSCs (Aim 2). These studies will
demonstrate the role of VPS4A and ESCRT-III machinery as an essential molecular pathway for erythropoiesis.

## Key facts

- **NIH application ID:** 10911266
- **Project number:** 5K01DK129270-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Katie Giger Seu
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $151,513
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911266

## Citation

> US National Institutes of Health, RePORTER application 10911266, Role of VPS4A and ESCRT-III in terminal erythropoiesis (5K01DK129270-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10911266. Licensed CC0.

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