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Mutations Affecting the Secretory COPII Coat Component SEC23B Cause Congenital Dyserythropoietic Anemia Type II

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Mutations Affecting the Secretory COPII Coat Component SEC23B Cause Congenital Dyserythropoietic Anemia Type II View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Archivio della ricerca - Università degli studi di Napoli Federico II LETTERS Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II Klaus Schwarz1,2,14, Achille Iolascon3,14, Fatima Verissimo4, Nikolaus S Trede5,6, Wyatt Horsley5,6, Wen Chen7, Barry H Paw7, Karl-Peter Hopfner8, Karlheinz Holzmann9, Roberta Russo3, Maria Rosaria Esposito3, Daniela Spano3, Luigia De Falco3, Katja Heinrich1, Brigitte Joggerst4, Markus T Rojewski1,2, Silverio Perrotta10, Jonas Denecke11, Ulrich Pannicke1, Jean Delaunay12, Rainer Pepperkok4 & Hermann Heimpel13 Congenital dyserythropoietic anemias (CDAs) are the parents are consanguinous (F2, F6, F11, F16, F18). Assuming a phenotypically and genotypically heterogeneous diseases1–4. recessive inheritance model, we conducted a screen for homozygous CDA type II (CDAII) is the most frequent CDA. It is chromosomal regions using genome-wide SNP analysis for individuals characterized by ineffective erythropoiesis and by the presence F6P1 and F11P1. This analysis revealed a single common homozygous of bi- and multinucleated erythroblasts in bone marrow, with region on chromosome 20p11.23–20p12.1 (Supplementary Table 2), nuclei of equal size and DNA content, suggesting a cytokinesis flanked by KIF16B on the telomeric side and SLC24A3 on the disturbance5. Other features of the peripheral red blood cells centromeric side and encompassing 23 ORFs. The CDAII locus was are protein and lipid dysglycosylation and endoplasmic originally mapped to 20q11 (ref. 8). In a refined contig build (build reticulum double-membrane remnants4,6. Development of 36.3), the markers with the highest CDAII lod scores overlap the other hematopoietic lineages is normal. Individuals with CDAII minimal homozygosity region on the short arm of chromosome 20 show progressive splenomegaly, gallstones and iron overload (ref. 9). The amalgamation of these results with the proposition of potentially with liver cirrhosis or cardiac failure. Here we show impaired cis, medial and trans N-glycan Golgi processing of erythro- that the gene encoding the secretory COPII component blast glycoproteins in CDAII10 made secretory pathway components SEC23B is mutated in CDAII. Short hairpin RNA (shRNA)- potential candidates. We therefore sequenced the SEC23B gene, which © All rights reserved. 2009 Inc. Nature America, mediated suppression of SEC23B expression recapitulates the is located in the critical region and encodes a COPII component, in all cytokinesis defect. Knockdown of zebrafish sec23b also leads 33 individuals. We detected 12 different missense mutations, five to aberrant erythrocyte development. Our results provide nonsense mutations, one single-nucleotide as well as one large in vivo evidence for SEC23B selectivity in erythroid deletion and one splice-site mutation (Fig. 1a and Supplementary differentiation and show that SEC23A and SEC23B, although Table 3). Seventeen individuals are compound heterozygotes, whereas highly related paralogous secretory COPII components, 16 individuals, including the eight in the five consanguinous families, are nonredundant in erythrocyte maturation. are homozygotes. Every case bears at least one missense mutation, suggesting that the presence of two severe mutations may be lethal. We studied 33 individuals with congenital dyserythropoietic anemia There are two hot spots of mutation, with 325G4A accounting for type II (CDAII; MIM224100) from 28 unrelated families (Supple- 30% (20 of 66 alleles) and 40C4T for 15% (10 of 66 alleles) of mentary Table 1) of various ancestral backgrounds. CDAII was the mutations. Haplotype analyses failed to demonstrate the existence diagnosed on the basis of previously published criteria7,including of a founder effect (data not shown). When data on parents were clinical aspects, bone marrow morphology and anomalous erythro- available, we found that parents were heterozygous for the muta- cyte membrane proteins (Supplementary Table 1). In five families, tions, excluding the occurrence of de novo mutations in these 1Institute for Transfusion Medicine, University of Ulm, Ulm, Germany. 2Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg-Hessen, Ulm, Germany. 3Department of Biochemistry and Medical Biotechnologies, University Federico II of Naples and CEINGE Advanced Biotechnologies, Naples, Italy. 4Cell Biology and Biophysics, European Molecular Biology Laboratory, Heidelberg, Germany. 5Huntsman Cancer Institute and 6Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA. 7Department of Medicine, Hematology Division, Brigham & Women’s Hospital, and Hematology-Oncology Division, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA. 8Center for Integrated Protein Science and Gene Center, Department of Chemistry and Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany. 9Chip Facility ZKF, University Hospital Ulm, Ulm, Germany. 10Department of Pediatrics, Second University of Naples, Naples, Italy. 11Department of Pediatrics, University of Rostock, Rostock, Germany. 12INSERM U 779, Hoˆpital de Biceˆtre, 94275 Le Kremlin-Biceˆtre, France. 13Department Internal Medicine III, University Hospital Ulm, Ulm, Germany. 14These authors contributed equally to this work. Correspondence should be addressed to K.S. ([email protected]) or A.I. ([email protected]). Received 12 March; accepted 1 June; published online 28 June 2009; doi:10.1038/ng.405 936 VOLUME 41 [ NUMBER 8 [ AUGUST 2009 NATURE GENETICS LETTERS Figure 1 SEC23B mutation analysis. (a) SEC23B a c BET1 binding site mutations are projected on the schematic domain R18H I318T Y462C A524V structure of SEC23B. Mutations are indicated in E109K R313H Q386R R497C A524V R18H Y462C blue when detected in more than one kindred. R14W D239G V426I R530W R14W 1 767 R530W (b) Upper panel shows SEC23B RT-PCR of normal and two affected individuals (F4P1, F6P1) ZNF TRUNKBS HE GEL Zinc finger fibroblasts, K562 cells and normal mononuclear SAR1 binding site V426I cells (MNC) of bone marrow (BM) and peripheral blood (pB). (For BM2, only 20% of RNA was R79X R217X R324X I318T used as compared to the other analyses. For MNC R264X R401X R313H E109K BM1, MNC BM2 and MNC pB, the gel loading c.689+1G>A D355IfsX8 R497C Q386R was doubled.) Lower panels show quantity of ∆ ex 3 + 4 SEC31 binding site SEC23B and total SEC23 protein as analyzed by SEC22 binding site protein blot in a control (C) and an affected D239G b individual (AI) cell line (F4P1). Quantification of SEC24 binding interface three independent experiments shows that the patient cell line has 38% ± 7% of SEC23B FibroblastsFibroblasts controlFibroblasts F4P1K562 F6P1MNC BM1MNC BM2MNC pBH2O SEC23B d compared to control. Total SEC23 is 67% ± 9% SEC23B ∆ex 3+4 of control. Tubulin detection was used as loading HPRT Neg. controlSEC23BSEC23B WT 1:20SEC23B WT 1:10 SEC23BWT 1:5SEC23B WT SEC23B E109KSEC23B R14W D239G control. (c) Model of human SEC23B shown as ribbon plot with highlighted secondary structure. SEC23B The model was generated on the basis of the anti-SEC23B anti-SEC23 crystal structure of human SEC23A. The side EGFP chains of mutated residues in SEC23B are shown SEC23B SEC23 as green spheres. Binding sites for known IP: anti-V5 16,23–25 anti-Tubulin e interaction partners are indicated . (d) Dilution analysis of SEC23B wild-type TUB and mutants overexpressed after transient AI C AI C SEC23B-myc transfections in HEK293T cells. The EGFP 24D/23B24D/23B WT24D/23B E109K24D/23B R14W24D/23B D239G24D/23B WT 24D/23B E109K24D/23B R14WNeg. D239G control ++++–– –– + signal is for the transfection and loading control. SEC24D-V5 WB (e) Coimmunoprecipitation of SEC23B wild-type anti-SEC23B anti-SEC23 SEC24D 120 120 and mutants. The presence (+) or absence (À)of 100 100 SEC23B the antibody to V5 is indicated. Protein G 80 80 sepharose Extracts 60 60 40 40 SEC24D 38% ± 7% of SEC23B, and total SEC23 was 20 20 67% ± 9% when normalized to the 100% in SEC23B Percentage of control signal Percentage of control signal 0 0 the control. C AIC AI The secretory pathway in eukaryotic cells is critical for membrane homeostasis, localiza- individuals and supporting autosomal recessive inheritance (Supple- tion of proteins within cells and secretion of extracellular factors. © All rights reserved. 2009 Inc. Nature America, mentary Table 3). The mutations affect most domains of SEC23B; During a budding reaction, cytoplasmic coat proteins (COPs) are only the C-terminal gelsolin-like domain is spared (Fig. 1a). All assembled on a membrane surface, capture cargo molecules and missense mutations affect highly conserved residues (Supplementary polymerize into a cage sculpting different-sized cargo vesicles. In Table 4). From our analyses, we conclude that most individuals with yeast, COPII-coated vesicles form by the sequential binding of Sar1- CDAII bear SEC23B mutations. GTP, the inner complex proteins Sec23–Sec24 and the outer complex In healthy subjects, the mutation 790C4T was heterozygously components Sec13–Sec31 on the endoplasmic reticulum (ER)11,12. detected once in 237 individuals, and the substitution 276G4Awas Sec23–Sec24 is implicated in selective cargo sorting destined for the present heterozygously 24 times in 354 subjects (6.7%). Changes cis-Golgi apparatus but has additional roles in completion of the coat present more than once in the cohort were
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