Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II.
Congenital dyserythropoietic anemias (CDAs) are phenotypically and genotypically heterogeneous diseases. CDA type II (CDAII) is the most frequent CDA. It is characterized by ineffective erythropoiesis and by the presence of bi- and multinucleated erythroblasts in bone marrow, with nuclei of equal size and DNA content, suggesting a cytokinesis disturbance. Other features of the peripheral red blood cells are protein and lipid dysglycosylation and endoplasmic reticulum double-membrane remnants. Development of other hematopoietic lineages is normal. Individuals with CDAII show progressive splenomegaly, gallstones and iron overload potentially with liver cirrhosis or cardiac failure. Here we show that the gene encoding the secretory COPII component SEC23B is mutated in CDAII. Short hairpin RNA (shRNA)-mediated suppression of SEC23B expression recapitulates the cytokinesis defect. Knockdown of zebrafish sec23b also leads to aberrant erythrocyte development. Our results provide in vivo evidence for SEC23B selectivity in erythroid differentiation and show that SEC23A and SEC23B, although highly related paralogous secretory COPII components, are nonredundant in erythrocyte maturation.
Schwarz
Klaus
K
Institute for Transfusion Medicine, University of Ulm, Ulm, Germany. klaus.schwarz@uni-ulm.de
Iolascon
Achille
A
Verissimo
Fatima
F
Trede
Nikolaus S
NS
Horsley
Wyatt
W
Chen
Wen
W
Paw
Barry H
BH
Hopfner
Karl-Peter
KP
Holzmann
Karlheinz
K
Russo
Roberta
R
Esposito
Maria Rosaria
MR
Spano
Daniela
D
De Falco
Luigia
L
Heinrich
Katja
K
Joggerst
Brigitte
B
Rojewski
Markus T
MT
Perrotta
Silverio
S
Denecke
Jonas
J
Pannicke
Ulrich
U
Delaunay
Jean
J
Pepperkok
Rainer
R
Heimpel
Hermann
H
D000742:Anemia, Dyserythropoietic, Congenital / Q000235:genetics*; D000818:Animals; D022181:COP-Coated Vesicles / Q000235:genetics*; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics; D004252:DNA Mutational Analysis; D041905:Erythroid Cells / Q000378:metabolism; D006801:Humans; D007568:Jaw / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D033921:Vesicular Transport Proteins / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics
C543353:SEC23B protein, human; D033921:Vesicular Transport Proteins