Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II

Abstract

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.

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

“…With the assumption that the cis, median and trans N-glycan Golgi processing of erythroblast glycoproteins was impaired, the SEC23B (CDAN2) gene became a likely candidate for CDA II. 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.…”

“…The specificity of the CDA II phenotype seems to be determined by tissue-specific expression of SEC23B versus SEC23A during erythroid differentiation. 67 Alternatively, this specificity could be explained by the presence of tissue-specific cargoes (such as band 3 in red blood cells), which might require high levels and full function of a specific COPII component to be correctly transported. 73 A recent study on 42 CDA II patients from the Italian and the French Registries showed a relationship between the mutations and various biological parameters.…”

“…Indeed, sec23b zebrafish morphants show a significant increase in immature, binucleated erythrocytes. 67 The disease gene encodes the cytoplasmic coat protein (COP)II component SEC23B, involved in the secretory pathway of eukaryotic cells. COPII is a multi-subunit complex which mediates accumulation of secretory cargo, deformation of the membrane and generation of subsequent anterograde transport of correctly folded cargo that bud from the ER towards the Golgi apparatus.…”

Compound heterozygosity for KLF1 mutations is associated with microcytic hypochromic anemia and increased fetal hemoglobin

“…8 Recent studies have attributed CDAII and CDAIII to mutations in SEC23B and KIF23, respectively. 9,10 A dominant mutation in the gene encoding the Krüppel-like factor 1 (KLF1) has been identified as the cause of the novel type IV CDA. Interestingly, all four documented cases were sporadic and carried the same de novo mutation c.973 A4G (p.(Glu325Lys)) in the second zinc finger (ZF) domain of KLF1.…”

Society for Pediatric Research 2015 Young Investigator Award: genetics of human hematopoiesis—what patients can teach us about blood cell production

“…For example, mice with mutations in Sec23b, whose orthologue is known to cause congenital dyserythropoietic anemia type II in humans, have completely normal blood counts and ostensibly normal red blood cell production (erythropoiesis) (11)(12)(13). In addition, there has also been an inability to develop faithful models for other congenital forms of anemia, such as Diamond-Blackfan anemia, which is characterized by a paucity of the earliest identifiable erythroid precursors with a reduction in erythroid-committed progenitors as well (14).…”