2. Academic Validation
  3. VPS4A Mutations in Humans Cause Syndromic Congenital Dyserythropoietic Anemia due to Cytokinesis and Trafficking Defects

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

  • Am J Hum Genet. 2020 Dec 3;107(6):1149-1156. doi: 10.1016/j.ajhg.2020.10.013.
Katie G Seu 1,  Lisa R Trump 2,  Sana Emberesh 2,  Robert B Lorsbach 3,  Clarissa Johnson 4,  Jessica Meznarich 5,  Hunter R Underhill 6,  Stella T Chou 7,  Haripriya Sakthivel 8,  Nicolas N Nassar 9,  Kalani J Seu 10,  Lionel Blanc 11,  Wenying Zhang 12,  Carolyn M Lutzko 13,  Theodosia A Kalfa 14
Affiliations

Affiliations

  • 1 Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address: katie.giger@cchmc.org.
  • 2 Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • 3 Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
  • 4 Pediatric Hematology-Oncology Cook Children's Medical Center, Fort Worth, TX 76104, USA.
  • 5 Division of Hematology-Oncology, Department of Pediatrics, University of Utah, Salt Lake City, UT 84132, USA; Primary Children's Hospital, Intermountain Healthcare, Salt Lake City, UT 84113, USA.
  • 6 Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84108, USA; Department of Radiology, University of Utah, Salt Lake City, UT 84108, USA.
  • 7 Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 8 Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • 9 Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
  • 10 Department of Chemistry, Earlham College, Richmond, IN 47374, USA.
  • 11 Laboratory of Developmental Erythropoiesis, Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA; Les Nelkin Memorial Pediatric Oncology Laboratory, Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA; Department of Molecular Medicine and Pediatrics, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA.
  • 12 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Laboratory of Genetics and Genomics, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • 13 Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
  • 14 Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. Electronic address: theodosia.kalfa@cchmc.org.
PMID: 33186543 DOI: 10.1016/j.ajhg.2020.10.013
Abstract

The Congenital Dyserythropoietic Anemia (CDA) Registry was established with the goal to facilitate investigations of natural history, biology, and molecular pathogenetic mechanisms of CDA. Three unrelated individuals enrolled in the registry had a syndrome characterized by CDA and severe neurodevelopmental delay. They were found to have missense mutations in VPS4A, a gene coding for an ATPase that regulates the ESCRT-III machinery in a variety of cellular processes including cell division, endosomal vesicle trafficking, and viral budding. Bone marrow studies showed binucleated erythroblasts and erythroblasts with cytoplasmic bridges indicating abnormal cytokinesis and abscission. Circulating red blood cells were found to retain Transferrin Receptor (CD71) in their membrane, demonstrating that VPS4A is critical for normal reticulocyte maturation. Using proband-derived induced pluripotent stem cells (iPSCs), we have successfully modeled the hematologic aspects of this syndrome in vitro, recapitulating their dyserythropoietic phenotype. Our findings demonstrate that VPS4A mutations cause cytokinesis and trafficking defects leading to a human disease with detrimental effects to erythropoiesis and neurodevelopment.

Keywords

ESCRT-III; VPS4A; congenital dyserythropoietic anemia; cytokinesis; erythropoiesis; hemolytic anemia; iPSCs; neurodevelopmental disorder; transferrin receptor; vesicle trafficking.

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