Characteristic phenotypes associated with congenital dyserythropoietic anemia (type II) manifest at different stages of erythropoiesis

Timothy J. Satchwell, Stephanie Pellegrin, Paola Bianchi, Bethan R. Hawley, Alexandra Gampel, Kathryn E. Mordue, Annika Budnik, Elisa Fermo, Wilma Barcellini, David J. Stephens, Emile van den Akker, Ashley M. Toye

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Congenital dyserythropoietic anemia type II is an autosomally recessive form of hereditary anemia caused by SEC23B gene mutations. Patients exhibit characteristic phenotypes including multinucleate erythroblasts, erythrocytes with hypoglycosylated membrane proteins and an apparent double plasma membrane. Despite ubiquitous expression of SEC23B, the effects of mutations in this gene are confined to the erythroid lineage and the basis of this erythroid specificity remains to be defined. In addition, little is known regarding the stage at which the disparate phenotypes of this disease manifest during erythropoiesis. We employ an in vitro culture system to monitor the appearance of the defining phenotypes associated with congenital dyserythropoietic anemia type II during terminal differentiation of erythroblasts derived from small volumes of patient peripheral blood. Membrane protein hypoglycosylation was detected by the basophilic stage, preceding the onset of multinuclearity in orthochromatic erythroblasts that occurs coincident with the loss of secretory pathway proteins including SEC23A during erythropoiesis. Endoplasmic reticulum remnants were observed in nascent reticulocytes of both diseased and healthy donor cultures but were lost upon further maturation of normal reticulocytes, implicating a defect of ER clearance during reticulocyte maturation in congenital dyserythropoietic anemia type II. We also demonstrate distinct isoform and species-specific expression profiles of SEC23 during terminal erythroid differentiation and identify a prolonged expression of SEC23A in murine erythropoiesis compared to humans. We propose that SEC23A is able to compensate for the absence of SEC23B in mouse erythroblasts, providing a basis for the absence of phenotype within the erythroid lineage of a recently described SEC23B knockout mouse.

Original languageEnglish
Pages (from-to)1788-1796
Number of pages9
JournalHaematologica
Volume98
Issue number11
DOIs
Publication statusPublished - Nov 1 2013

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Congenital Dyserythropoietic Anemia
Erythroblasts
Erythropoiesis
Reticulocytes
Phenotype
Membrane Proteins
Mutation
Secretory Pathway
Knockout Mice
Endoplasmic Reticulum
Genes
Anemia
Protein Isoforms
Erythrocytes
Cell Membrane
Tissue Donors
Proteins

ASJC Scopus subject areas

  • Hematology

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Characteristic phenotypes associated with congenital dyserythropoietic anemia (type II) manifest at different stages of erythropoiesis. / Satchwell, Timothy J.; Pellegrin, Stephanie; Bianchi, Paola; Hawley, Bethan R.; Gampel, Alexandra; Mordue, Kathryn E.; Budnik, Annika; Fermo, Elisa; Barcellini, Wilma; Stephens, David J.; van den Akker, Emile; Toye, Ashley M.

In: Haematologica, Vol. 98, No. 11, 01.11.2013, p. 1788-1796.

Research output: Contribution to journalArticle

Satchwell, TJ, Pellegrin, S, Bianchi, P, Hawley, BR, Gampel, A, Mordue, KE, Budnik, A, Fermo, E, Barcellini, W, Stephens, DJ, van den Akker, E & Toye, AM 2013, 'Characteristic phenotypes associated with congenital dyserythropoietic anemia (type II) manifest at different stages of erythropoiesis', Haematologica, vol. 98, no. 11, pp. 1788-1796. https://doi.org/10.3324/haematol.2013.085522
Satchwell, Timothy J. ; Pellegrin, Stephanie ; Bianchi, Paola ; Hawley, Bethan R. ; Gampel, Alexandra ; Mordue, Kathryn E. ; Budnik, Annika ; Fermo, Elisa ; Barcellini, Wilma ; Stephens, David J. ; van den Akker, Emile ; Toye, Ashley M. / Characteristic phenotypes associated with congenital dyserythropoietic anemia (type II) manifest at different stages of erythropoiesis. In: Haematologica. 2013 ; Vol. 98, No. 11. pp. 1788-1796.
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AU - Gampel, Alexandra

AU - Mordue, Kathryn E.

AU - Budnik, Annika

AU - Fermo, Elisa

AU - Barcellini, Wilma

AU - Stephens, David J.

AU - van den Akker, Emile

AU - Toye, Ashley M.

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AB - Congenital dyserythropoietic anemia type II is an autosomally recessive form of hereditary anemia caused by SEC23B gene mutations. Patients exhibit characteristic phenotypes including multinucleate erythroblasts, erythrocytes with hypoglycosylated membrane proteins and an apparent double plasma membrane. Despite ubiquitous expression of SEC23B, the effects of mutations in this gene are confined to the erythroid lineage and the basis of this erythroid specificity remains to be defined. In addition, little is known regarding the stage at which the disparate phenotypes of this disease manifest during erythropoiesis. We employ an in vitro culture system to monitor the appearance of the defining phenotypes associated with congenital dyserythropoietic anemia type II during terminal differentiation of erythroblasts derived from small volumes of patient peripheral blood. Membrane protein hypoglycosylation was detected by the basophilic stage, preceding the onset of multinuclearity in orthochromatic erythroblasts that occurs coincident with the loss of secretory pathway proteins including SEC23A during erythropoiesis. Endoplasmic reticulum remnants were observed in nascent reticulocytes of both diseased and healthy donor cultures but were lost upon further maturation of normal reticulocytes, implicating a defect of ER clearance during reticulocyte maturation in congenital dyserythropoietic anemia type II. We also demonstrate distinct isoform and species-specific expression profiles of SEC23 during terminal erythroid differentiation and identify a prolonged expression of SEC23A in murine erythropoiesis compared to humans. We propose that SEC23A is able to compensate for the absence of SEC23B in mouse erythroblasts, providing a basis for the absence of phenotype within the erythroid lineage of a recently described SEC23B knockout mouse.

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