Congenital dyserythropoietic anemia type II (CDAII) is caused by mutations in theSEC23Bgene

Abstract

Congenital dyserythropoietic anemia type II (CDAII) is an autosomal recessive disease characterized by ineffective erythropoiesis, hemolysis, erythroblast morphological abnormalities, and hypoglycosylation of some red blood cell (RBC) membrane proteins. Recent studies indicated that CDAII is caused by a defect disturbing Golgi processing in erythroblasts. A linkage analysis located a candidate region on chromosome 20, termed the CDAN2 locus, in the majority of CDAII patients but the aberrant gene has not so far been elucidated. We used a proteomic-genomic approach to identify SEC23B as the candidate gene for CDAII by matching the recently published data on the cytoplasmic proteome of human RBCs with the chromosomic localization of CDAN2 locus. Sequencing analysis of SEC23B gene in 13 CDAII patients from 10 families revealed 12 different mutations: six missense (c.40C>T, c.325G>A, c.1043A>C, c.1489C>T, c.1808C>T, and c.2101C>T), two frameshift (c.428_428delAinsCG and c.1821delT), one splicing (c.689+1G>A), and three nonsense (c.568C>T, c.649C>T, and c.1660C>T). Mutations c.40C>T and c.325G>A were detected in unrelated patients. SEC23B is a member of the Sec23/Sec24 family, a component of the COPII coat protein complex involved in protein transport through membrane vesicles. Abnormalities in this gene are likely to disturb endoplasmic reticulum (ER)-to-Golgi trafficking, affecting different glycosylation pathways and ultimately accounting for the cellular phenotype observed in CDAII.

Loss of autophagy in erythroid cells leads to defective removal of mitochondria and severe anemia in vivo

“…First, congenital dyserythropoietic anemia type II (CDAII) is a rare anemia, in which double membranes are found in a large proportion of red cell precursors (34). However, as the molecular basis of CDAII has just been elucidated (35,36), an important role for autophagy in the pathogenesis of this disease is now unlikely. Second, myelodysplastic syndrome (MDS) comprises a group of anemic disorders characterized by abnormal cell morphology in the bone marrow accompanied by cytopenias in peripheral blood.…”

Congenital dyserythropoietic anemia type II (CDA II) diagnosed in an adult patient

“…According to previously proposed classification schemes [24,25], confirmation of CDA II includes sodium dodecyl sulfate polyacrylamide gel electrophoresis for erythrocyte band 3 protein [26], acidified serum lysis testing (HAM's test) [16], electron microscopy to demonstrate the presence of a double membrane adjacent the cell membrane in mature red blood cells [27], or assessment of mutation status of the recently recognized SEC3B gene [12]. These specialized tests, however, are not available in most clinical laboratories.…”

“…Genome-wide linkage analysis relegated genetic mutations to the long arm of chromosome 20 in a region referred as the CDAN 2 locus [10]; however, the majority of specific candidate genes within this region had been excluded [11]. As recently as 2009, investigators have demonstrated that CDA II is caused by missense mutations in the SEC23B gene encoding coat protein complex II (COPII), complex proteins critical for membrane homeostasis and vesicular trafficking from the endoplasmic reticulum to the golgi complex in eukaryotes [12]. Disruption of SEC23B gene expression has been shown to recapitulate the nuclear cytokinesis and double cell membrane defects characteristic of CDA II erythroblasts [13,14].…”

Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach

“…67 A proteomic approach led to the same result. 68 Sequencing analysis in 33 patients from 28 unrelated families from the main European Registries showed a wide spectrum of different mutations in the SEC23B gene in either the compound heterozygous or homozygous state. 67 In the same study, an in vitro model of gene silencing demonstrated that suppression of SEC23B expression recapitulates the cytokinesis defect, with a significant increase in the percentage of binuclearity and an increased size of nuclei in SEC23B silenced cells.…”