Mutational spectrum in congenital dyserythropoietic anemia type II: Identification of 19 novel variants in SEC23B gene

Roberta Russo,Vedat Uygun,Gian Luca Forni,Antonella Gambale,Ugo Ramenghi,Jean Delaunay,Roberta Asci,Achille Iolascon,Silverio Perrotta,Maria Rosaria Esposito

doi:10.1002/ajh.21866

Abstract

SEC23B gene encodes an essential component of the coat protein complex II (COPII)-coated vesicles. Mutations in this gene cause the vast majority the congenital dyserythropoietic anemia Type II (CDA II), a rare disorder resulting from impaired erythropoiesis. Here, we investigated 28 CDA II patients from 21 unrelated families enrolled in the CDA II International Registry. Overall, we found 19 novel variants [c.2270 A>C p.H757P; c.2149−2 A>G; c.1109+1 G>A; c.387(delG) p.L129LfsX26; c.1858 A>G p.M620V; c.1832 G>C p.R611P; c.1735 T>A p.Y579N; c.1254 T>G p.I418M; c.1015 C>T p.R339X; c.1603 C>T p.R535X; c.1654 C>T p.L552F; c.1307 C>T p.S436L; c.279+3 A>G; c. 2150(delC) p.A717VfsX7; c.1733 T>C p.L578P; c.1109+5 G>A; c.221+31 A>G; c.367 C>T p.R123X; c.1857_1859delCAT; p.I619del] in the homozygous or the compound heterozygous state. Homozygosity or compound heterozygosity for two nonsense mutations was never found. In four cases the sequencing analysis has failed to find two mutations. To discuss the putative functional consequences of missense mutations, computational analysis and sequence alignment were performed. Our data underscore the high allelic heterogeneity of CDA II, as the most of SEC23B variations are inherited as private mutations. In this mutation update, we also provided a tool to improve and facilitate the molecular diagnosis of CDA II by defining the frequency of mutations in each exon. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc.

Highlights

Mutations in the SEC23B gene (Sec23 homolog B; MIM#610512, 20p11.23) cause the vast majority of the congenital dyserythropoietic anemia Type II (CDA II MIM# %224100), an autosomal recessive disorder that represents the most common form of CDAs
Extensive morphological anomalies of CDA-II erythroblastic cells were observed using electron microscopy (EM), with the most significant being the presence of the so-called double membrane, which is observable in mature red blood cells (RBC) as well [6,7]
For most of all patients SDS-PAGE revealed the typical narrower band size and faster migration of the band 3 and band 4.5 proteins; the diagnosis has been confirmed by the demonstration of superficial appearance of reticulum-endothelial protein GRP78 on membrane proteins by Western blot (WB)

Summary

Introduction

Mutations in the SEC23B gene (Sec homolog B; MIM#610512, 20p11.23) cause the vast majority of the congenital dyserythropoietic anemia Type II (CDA II MIM# %224100), an autosomal recessive disorder that represents the most common form of CDAs. Extensive morphological anomalies of CDA-II erythroblastic cells were observed using electron microscopy (EM), with the most significant being the presence of the so-called double membrane, which is observable in mature RBCs as well [6,7]. This typical aspect is due to residual endoplasmic reticulum [8]. Polyacrylamide gel electrophoresis in presence of sodium dodecyl sulphate (SDS-PAGE) revealed the presence of a thinner band 3 with an increased anodic mobility due to reduced glycosylation This cardinal abnormality represents a key for the diagnosis [9] and could suggest a defect in vesicles trafficking

Methods

Results

Conclusion