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VPS4A Mutations in Humans Cause Syndromic Congenital Dyserythropoietic Anemia due to Cytokinesis and Trafficking

Katie G Seu1, Lisa R Trump2, Sana Emberesh2

  • 1Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

American Journal of Human Genetics
|November 13, 2020
PubMed

Insights

Mutations in the VPS4A gene cause Congenital Dyserythropoietic Anemia (CDA) and severe neurodevelopmental delay by disrupting cell division and maturation processes. This research highlights VPS4A

Area of Science:

  • Genetics
  • Hematology
  • Cell Biology

Background:

  • Congenital Dyserythropoietic Anemia (CDA) is a group of rare inherited blood disorders.
  • Understanding the molecular basis of CDA is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the genetic and molecular mechanisms underlying a specific CDA syndrome with severe neurodevelopmental delay.
  • To identify the gene responsible for the observed phenotype and elucidate its role in erythropoiesis and neurodevelopment.

Main Methods:

  • Analysis of three unrelated individuals with CDA and neurodevelopmental delay.
  • Whole-exome sequencing to identify genetic mutations.
  • Bone marrow morphology studies.
  • Induced pluripotent stem cell (iPSC) modeling to recapitulate disease phenotype in vitro.

Main Results:

  • Identified missense mutations in the VPS4A gene in all affected individuals.
  • VPS4A mutations were linked to defects in cytokinesis and endosomal trafficking.
  • Observed abnormal erythroblast morphology (binucleation, cytoplasmic bridges) and impaired reticulocyte maturation (transferrin receptor retention).
  • Proband-derived iPSCs successfully modeled the hematologic aspects of the syndrome.

Conclusions:

  • VPS4A mutations are causative of a novel CDA syndrome with severe neurodevelopmental impairment.
  • VPS4A plays a critical role in cell division, trafficking, erythropoiesis, and neurodevelopment.
  • The study provides a cellular model for investigating VPS4A-related disorders.

Keywords:
ESCRT-IIIVPS4Acongenital dyserythropoietic anemiacytokinesiserythropoiesishemolytic anemiaiPSCsneurodevelopmental disordertransferrin receptorvesicle trafficking

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