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

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.

VPS4A mutation in syndromic congenital hemolytic anemia without obvious signs of dyserythropoiesis

“…He was the first child of healthy blasts and red blood cells. 1,2 In our patient, the absence of obvious cytologic signs of CDA in bone marrow contrasts with the hematological findings in patients described by Seu et al, including one with the same mutation, which all had clear CDA. 1 This discrepancy could be due in part to the fact that patients reported by Seu et al were included through the congenital dyserythropoietic anemia registry for North America (CDAR).…”

“…Very recently, two research groups described a new neurodevelopmental syndrome with hematologic impairment, caused by de novo dominant mutations in the VPS4A gene. 1,2 Seu et al focused on three cases characterized by Congenital Dyserythropoietic Anemia (CDA) associated with a severe neurodevelopmental disorder (global developmental delay with microcephaly, retinal dystrophy and cerebellar hypoplasia; ref. 2 Rodger et al focused on the neurodevelopmental disorder whereas hematological parameters were not extensively described.…”

“…1,2 Seu et al focused on three cases characterized by Congenital Dyserythropoietic Anemia (CDA) associated with a severe neurodevelopmental disorder (global developmental delay with microcephaly, retinal dystrophy and cerebellar hypoplasia; ref. 2 Rodger et al focused on the neurodevelopmental disorder whereas hematological parameters were not extensively described. 1 The VPS4A protein is a vacuolar ATPase involved in reticulocyte maturation through exosome biogenesis.…”

“…The same mutation had previously been found in five out of nine identified patients with VPS4Arelated disorder. 1,2 Functional testing of the p.R284W variant had been performed, showing a deleterious effect of mutated VPS4A protein on endosomal trafficking, formation of centrosome, primary cilium morphology and regulation of cell cycle in patients' fibroblasts and red blood cells. 1,2 In our patient, the absence of obvious cytologic signs of CDA in bone marrow contrasts with the hematological findings in patients described by Seu et al, including one with the same mutation, which all had clear CDA.…”

A rare congenital anemia is caused by mutations in the centralspindlin complex

“…CDAs were classically distinguished into three major types based on erythroblast morphology in the bone marrow; a fourth type emerged that encompassing atypical morphologies (1,2). The genetic etiology of these disorders include mutations in CDAN1 or C15ORF41 for CDAI (3,4), SEC23B for CDAII (5,6), KIF23 for CDAIII (7), and KLF1, GATA1, ALAS2, or VPS4A for some of the CDA variants (8)(9)(10)(11). CDAIII is the rarest form with ~60 patients described.…”