RBCC

Full text data of SEC23B

SEC23B [Confidence: low (only semi-automatic identification from reviews)]
Protein transport protein Sec23B (SEC23-related protein B)

UniProt Q15437
ID SC23B_HUMAN Reviewed; 767 AA.
AC Q15437; D3DW33; Q503A9; Q5W183; Q9BS15; Q9BSI2; Q9H1D7;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2002, sequence version 2.
DT 22-JAN-2014, entry version 124.
DE RecName: Full=Protein transport protein Sec23B;
DE AltName: Full=SEC23-related protein B;
GN Name=SEC23B;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT GLN-489.
RC TISSUE=B-cell;
RX PubMed=8898360; DOI=10.1091/mbc.7.10.1535;
RA Paccaud J.-P., Reith W., Carpentier J.-L., Ravazzola M., Amherdt M.,
RA Schekman R., Orci L.;
RT "Cloning and functional characterization of mammalian homologues of
RT the COPII component Sec23.";
RL Mol. Biol. Cell 7:1535-1546(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS VAL-373 AND
RP LEU-433.
RC TISSUE=Cervix, Placenta, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [7]
RP VARIANTS CDA2 TRP-14; LYS-109; ALA-348; CYS-497; LEU-603 AND CYS-701,
RP AND VARIANT GLN-489.
RX PubMed=19621418; DOI=10.1002/humu.21077;
RA Bianchi P., Fermo E., Vercellati C., Boschetti C., Barcellini W.,
RA Iurlo A., Marcello A.P., Righetti P.G., Zanella A.;
RT "Congenital dyserythropoietic anemia type II (CDAII) is caused by
RT mutations in the SEC23B gene.";
RL Hum. Mutat. 30:1292-1298(2009).
RN [8]
RP VARIANTS CDA2 TRP-14; LYS-109 AND TRP-530, VARIANTS HIS-18; GLY-239;
RP HIS-313; THR-318; ARG-386; ILE-426; CYS-462; CYS-497 AND VAL-524,
RP CHARACTERIZATION OF VARIANTS CDA2 TRP-14 AND LYS-109, AND
RP CHARACTERIZATION OF VARIANT GLY-239.
RX PubMed=19561605; DOI=10.1038/ng.405;
RA Schwarz K., Iolascon A., Verissimo F., Trede N.S., Horsley W.,
RA Chen W., Paw B.H., Hopfner K.-P., Holzmann K., Russo R.,
RA Esposito M.R., Spano D., De Falco L., Heinrich K., Joggerst B.,
RA Rojewski M.T., Perrotta S., Denecke J., Pannicke U., Delaunay J.,
RA Pepperkok R., Heimpel H.;
RT "Mutations affecting the secretory COPII coat component SEC23B cause
RT congenital dyserythropoietic anemia type II.";
RL Nat. Genet. 41:936-940(2009).
CC -!- FUNCTION: Component of the COPII coat, that covers ER-derived
CC vesicles involved in transport from the endoplasmic reticulum to
CC the Golgi apparatus. COPII acts in the cytoplasm to promote the
CC transport of secretory, plasma membrane, and vacuolar proteins
CC from the endoplasmic reticulum to the Golgi complex (By
CC similarity).
CC -!- SUBUNIT: COPII is composed of at least five proteins: the Sec23/24
CC complex, the Sec13/31 complex and Sar1 (By similarity).
CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane (By similarity).
CC Endoplasmic reticulum membrane (By similarity). Endoplasmic
CC reticulum-Golgi intermediate compartment membrane (By similarity).
CC -!- DISEASE: Congenital dyserythropoietic anemia 2 (CDA2)
CC [MIM:224100]: An autosomal recessive blood disorder characterized
CC by morphological abnormalities of erythroblasts, ineffective
CC erythropoiesis, normocytic anemia, iron overload, jaundice, and
CC variable splenomegaly. Ultrastructural features include bi- or
CC multinucleated erythroblasts in bone marrow, karyorrhexis, and the
CC presence of Gaucher-like bone marrow histiocytes. The main
CC biochemical feature of the disease is defective glycosylation of
CC some red blood cells membrane proteins. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the SEC23/SEC24 family. SEC23 subfamily.
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DR EMBL; X97065; CAA65775.1; -; mRNA.
DR EMBL; AL121893; CAI12512.1; -; Genomic_DNA.
DR EMBL; AL121900; CAI12512.1; JOINED; Genomic_DNA.
DR EMBL; AL121900; CAH73149.1; -; Genomic_DNA.
DR EMBL; AL121893; CAH73149.1; JOINED; Genomic_DNA.
DR EMBL; CH471133; EAX10231.1; -; Genomic_DNA.
DR EMBL; CH471133; EAX10232.1; -; Genomic_DNA.
DR EMBL; CH471133; EAX10233.1; -; Genomic_DNA.
DR EMBL; CH471133; EAX10234.1; -; Genomic_DNA.
DR EMBL; CH471133; EAX10235.1; -; Genomic_DNA.
DR EMBL; BC005032; AAH05032.1; -; mRNA.
DR EMBL; BC005404; AAH05404.1; -; mRNA.
DR EMBL; BC095404; AAH95404.1; -; mRNA.
DR RefSeq; NP_001166216.1; NM_001172745.1.
DR RefSeq; NP_001166217.1; NM_001172746.1.
DR RefSeq; NP_006354.2; NM_006363.4.
DR RefSeq; NP_116780.1; NM_032985.4.
DR RefSeq; NP_116781.1; NM_032986.3.
DR UniGene; Hs.369373; -.
DR ProteinModelPortal; Q15437; -.
DR SMR; Q15437; 3-764.
DR IntAct; Q15437; 12.
DR MINT; MINT-3031478; -.
DR STRING; 9606.ENSP00000262544; -.
DR PhosphoSite; Q15437; -.
DR DMDM; 20141794; -.
DR PaxDb; Q15437; -.
DR PeptideAtlas; Q15437; -.
DR PRIDE; Q15437; -.
DR DNASU; 10483; -.
DR Ensembl; ENST00000262544; ENSP00000262544; ENSG00000101310.
DR Ensembl; ENST00000336714; ENSP00000338844; ENSG00000101310.
DR Ensembl; ENST00000377465; ENSP00000366685; ENSG00000101310.
DR Ensembl; ENST00000377475; ENSP00000366695; ENSG00000101310.
DR GeneID; 10483; -.
DR KEGG; hsa:10483; -.
DR UCSC; uc002wqz.2; human.
DR CTD; 10483; -.
DR GeneCards; GC20P018488; -.
DR HGNC; HGNC:10702; SEC23B.
DR HPA; HPA008216; -.
DR MIM; 224100; phenotype.
DR MIM; 610512; gene.
DR neXtProt; NX_Q15437; -.
DR Orphanet; 98873; Congenital dyserythropoietic anemia type 2.
DR PharmGKB; PA35625; -.
DR eggNOG; COG5047; -.
DR HOVERGEN; HBG055039; -.
DR InParanoid; Q15437; -.
DR KO; K14006; -.
DR OMA; HNAPVPQ; -.
DR OrthoDB; EOG72C4ZP; -.
DR PhylomeDB; Q15437; -.
DR ChiTaRS; SEC23B; human.
DR GeneWiki; SEC23B; -.
DR GenomeRNAi; 10483; -.
DR NextBio; 39772; -.
DR PRO; PR:Q15437; -.
DR ArrayExpress; Q15437; -.
DR Bgee; Q15437; -.
DR CleanEx; HS_SEC23B; -.
DR Genevestigator; Q15437; -.
DR GO; GO:0030127; C:COPII vesicle coat; IEA:InterPro.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0033116; C:endoplasmic reticulum-Golgi intermediate compartment membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0016020; C:membrane; TAS:ProtInc.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006888; P:ER to Golgi vesicle-mediated transport; IEA:InterPro.
DR GO; GO:0006886; P:intracellular protein transport; IEA:InterPro.
DR GO; GO:0016192; P:vesicle-mediated transport; TAS:ProtInc.
DR Gene3D; 3.40.50.410; -; 1.
DR InterPro; IPR007123; Gelsolin_dom.
DR InterPro; IPR006900; Sec23/24_helical_dom.
DR InterPro; IPR006896; Sec23/24_trunk_dom.
DR InterPro; IPR012990; Sec23_24_beta_S.
DR InterPro; IPR002035; VWF_A.
DR InterPro; IPR006895; Znf_Sec23_Sec24.
DR Pfam; PF00626; Gelsolin; 1.
DR Pfam; PF08033; Sec23_BS; 1.
DR Pfam; PF04815; Sec23_helical; 1.
DR Pfam; PF04811; Sec23_trunk; 1.
DR Pfam; PF04810; zf-Sec23_Sec24; 1.
DR SUPFAM; SSF81811; SSF81811; 1.
DR SUPFAM; SSF82919; SSF82919; 1.
PE 1: Evidence at protein level;
KW Acetylation; Complete proteome; Congenital dyserythropoietic anemia;
KW Disease mutation; Endoplasmic reticulum; ER-Golgi transport;
KW Golgi apparatus; Hereditary hemolytic anemia; Membrane; Polymorphism;
KW Protein transport; Reference proteome; Transport.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 767 Protein transport protein Sec23B.
FT /FTId=PRO_0000205148.
FT MOD_RES 2 2 N-acetylalanine.
FT VARIANT 14 14 R -> W (in CDA2; the mutant protein is
FT unstable with less than 5% of protein
FT detectable compared to wild-type).
FT /FTId=VAR_062294.
FT VARIANT 18 18 R -> H.
FT /FTId=VAR_062295.
FT VARIANT 109 109 E -> K (in CDA2; the mutant protein is
FT unstable with less than 5% of protein
FT detectable compared to wild-type).
FT /FTId=VAR_062296.
FT VARIANT 239 239 D -> G (the mutant protein is expressed
FT as the wild-type).
FT /FTId=VAR_062297.
FT VARIANT 313 313 R -> H.
FT /FTId=VAR_062298.
FT VARIANT 318 318 I -> T.
FT /FTId=VAR_062299.
FT VARIANT 348 348 D -> A (in CDA2).
FT /FTId=VAR_062300.
FT VARIANT 373 373 M -> V (in dbSNP:rs17849992).
FT /FTId=VAR_062301.
FT VARIANT 386 386 Q -> R.
FT /FTId=VAR_062302.
FT VARIANT 426 426 V -> I (in dbSNP:rs41309927).
FT /FTId=VAR_062303.
FT VARIANT 433 433 P -> L (in dbSNP:rs17807673).
FT /FTId=VAR_034482.
FT VARIANT 462 462 Y -> C.
FT /FTId=VAR_062304.
FT VARIANT 489 489 H -> Q (in dbSNP:rs2273526).
FT /FTId=VAR_020318.
FT VARIANT 497 497 R -> C (in CDA2; unknown pathological
FT significance).
FT /FTId=VAR_062305.
FT VARIANT 524 524 A -> V.
FT /FTId=VAR_062306.
FT VARIANT 530 530 R -> W (in CDA2).
FT /FTId=VAR_062307.
FT VARIANT 603 603 S -> L (in CDA2).
FT /FTId=VAR_062308.
FT VARIANT 701 701 R -> C (in CDA2; dbSNP:rs201270568).
FT /FTId=VAR_062309.
SQ SEQUENCE 767 AA; 86479 MW; 1A00DE39D56B0204 CRC64;
MATYLEFIQQ NEERDGVRFS WNVWPSSRLE ATRMVVPLAC LLTPLKERPD LPPVQYEPVL
CSRPTCKAVL NPLCQVDYRA KLWACNFCFQ RNQFPPAYGG ISEVNQPAEL MPQFSTIEYV
IQRGAQSPLI FLYVVDTCLE EDDLQALKES LQMSLSLLPP DALVGLITFG RMVQVHELSC
EGISKSYVFR GTKDLTAKQI QDMLGLTKPA MPMQQARPAQ PQEHPFASSR FLQPVHKIDM
NLTDLLGELQ RDPWPVTQGK RPLRSTGVAL SIAVGLLEGT FPNTGARIML FTGGPPTQGP
GMVVGDELKI PIRSWHDIEK DNARFMKKAT KHYEMLANRT AANGHCIDIY ACALDQTGLL
EMKCCANLTG GYMVMGDSFN TSLFKQTFQR IFTKDFNGDF RMAFGATLDV KTSRELKIAG
AIGPCVSLNV KGPCVSENEL GVGGTSQWKI CGLDPTSTLG IYFEVVNQHN TPIPQGGRGA
IQFVTHYQHS STQRRIRVTT IARNWADVQS QLRHIEAAFD QEAAAVLMAR LGVFRAESEE
GPDVLRWLDR QLIRLCQKFG QYNKEDPTSF RLSDSFSLYP QFMFHLRRSP FLQVFNNSPD
ESSYYRHHFA RQDLTQSLIM IQPILYSYSF HGPPEPVLLD SSSILADRIL LMDTFFQIVI
YLGETIAQWR KAGYQDMPEY ENFKHLLQAP LDDAQEILQA RFPMPRYINT EHGGSQARFL
LSKVNPSQTH NNLYAWGQET GAPILTDDVS LQVFMDHLKK LAVSSAC
//

MIM 224100
*RECORD*
*FIELD* NO
224100
*FIELD* TI
#224100 ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE II; CDAN2
;;DYSERYTHROPOIETIC ANEMIA, CONGENITAL, TYPE II;;
read moreCDA II;;
DYSERYTHROPOIETIC ANEMIA, HEMPAS TYPE;;
HEREDITARY ERYTHROBLASTIC MULTINUCLEARITY WITH POSITIVE ACIDIFIED-SERUM
TEST; HEMPAS
*FIELD* TX
A number sign (#) is used with this entry because congenital
dyserythropoietic anemia type II (CDAN2) is caused by homozygous or
compound heterozygous mutation in the SEC23B gene (610512) on chromosome
20p11.

For a general description and a discussion of genetic heterogeneity of
CDA, see CDAN1 (224120).

CLINICAL FEATURES

Verwilghen et al. (1969) reported 2 families. De Lozzio et al. (1962)
studied an affected woman with 2 affected sisters. The parents could not
be examined. They demonstrated endopolyploidy by chromosome studies of
bone marrow. The karyotype of skin cells was normal. They pointed out
that several instances are known in plants and animals where the mitotic
process is influenced by mutant genes. Crookston et al. (1969) observed
5 patients, including 2 sisters, with what appeared to be the same
disorder: anemia characterized by multiple nuclei in erythroblasts,
ineffective erythropoiesis, and lysis of red cells by acidified serum
from some persons.

Enquist et al. (1972) described 3 cases in a sibship of 10. They
described the occurrence of Gaucher-like histiocytes in bone marrow,
resembling those seen in chronic myelogenous leukemia and thalassemia.
They made the important observation that heterozygotes may show some of
the serologic abnormalities of HEMPAS without clinical disease.
Increased susceptibility to lysis by anti-I antibody (110800) is a
feature of HEMPAS. Lowenthal et al. (1980) reported an atypical case in
a man who was the product of a first-cousin Anglo-Saxon marriage and
whose twin brother was also affected. At age 43 years, the man showed 2
unusual features: severe tophaceous gout and massive splenomegaly.
Hematologic peculiarities suggested that the disorder in the twins
represented a distinct form of congenital dyserythropoietic anemia.

In a retrospective study of 41 patients with CDA II, Perrotta et al.
(2000) found that patients with coinheritance of Gilbert syndrome
(143500) had a significantly increased risk of hyperbilirubinemia and
gallstone formation and a significantly earlier age at diagnosis of
gallstones.

Iolascon et al. (2001) reviewed data on 98 patients from unrelated
families enrolled in the International Registry of CDA II. The mean age
at presentation was 5.2 +/- 6.1 years. Anemia was present in 66% and
jaundice in 53.4% of cases. The mean age at correct diagnosis was 15.9
+/- 11.8 years. In 23% of patients for whom data were available, anemia
developed during the neonatal period, and 10 of these individuals
required transfusions. Splenectomy produced an increased hemoglobin (P
less than 0.001) and a reduced bilirubin level (P = 0.007) in comparison
with values before splenectomy. Preliminary data indicated that iron
overload occurs irrespective of the hemochromatosis genotype.

Bianchi et al. (2009) reported 13 patients from 10 unrelated families
with CDA type II. Eleven patients were Italian, 1 was Bolivian, and 1
was Rumanian. The age at diagnosis ranged from 2 to 54 years. Variable
but common features included splenomegaly with splenectomy, blood
transfusion, cholelithiasis, cholecystectomy, anemia, increased
reticulocytes, increased unconjugated bilirubin, increased erythrocyte
osmotic fragility, and hypoglycosylation of red blood cells. Only 1
patient had neonatal jaundice.

BIOCHEMICAL FEATURES

CDA Type II, which is also known as 'hereditary erythroblastic
multinuclearity with a positive acidified serum (HEMPAS) test,' is
distinguished by a positive acidified serum test and increased red cell
lysis on exposure to both anti-i and anti-I antibody (110800) (Wendt and
Heimpel, 1967).

Baines et al. (1982) found an electrophoretic abnormality of the
preponderant integral membrane protein, band 3--specifically in the
extracellular domain of the protein, which is the glycosylated part. The
finding correlates with morphologic changes in the cell membrane of the
late erythroblast. Fukuda et al. (1984) found that band 3 and band 4.5
of the red cell membrane are not glycosylated by lactosaminoglycans in
HEMPAS erythrocytes, whereas normally these proteins have
lactosaminoglycans. By analyzing the carbohydrate structure of HEMPAS
band 3, Fukuda et al. (1987) demonstrated the point at which
glycosylation of lactosaminoglycans stops. They showed further that the
enzyme N-acetylglucosaminyltransferase II, which functions at the site
of the block, is deficient in patients with HEMPAS and suggested that
this is the primary defect. They concluded that, to date, HEMPAS is
unique among inborn errors of metabolism in that it is a defect in
biosynthesis of a glycoprotein.

Fukuda et al. (1990) studied a new case (G.C.) of HEMPAS which changed
their thinking about the nature of the basic defect in the disorder.
Enzyme defect in most HEMPAS patients had previously been proposed as a
lowered activity of N-acetylglucosaminyltransferase II, resulting in a
lack of polylactosamine on proteins and leading to the accumulation of
polylactosaminyl lipids. Fukuda et al. (1990) found that G.C. cells
showed significantly decreased glycosylation of polylactosaminyl glycan
proteins and incompletely processed asparagine-linked oligosaccharides
in erythrocyte membranes. In contrast to the earlier studied cases, G.C.
cells were normal in N-acetylglucosaminyltransferase II activity but
were low in alpha-mannosidase II (alpha-ManII) activity . Northern (RNA)
analysis of poly(A)+ mRNA from normal, G.C., and other unrelated HEMPAS
cells all showed double bands at the 7.6-kb position, detected by an
alpha-ManII cDNA probe, but expression of these bands in G.C. cells was
reduced to less than 10% of normal. In Southern analysis of G.C. and
normal genomic DNA, the restriction fragment patterns detected by the
alpha-ManII cDNA probe were indistinguishable. The results were
interpreted as suggesting that G.C. cells contained a mutation in the
alpha-ManII-encoding gene that results in inefficient expression of
alpha-ManII mRNA, either through reduced transcription or message
instability. Thus, the authors concluded that HEMPAS is caused by a
defective gene encoding an enzyme necessary for the synthesis of
asparagine-linked oligosaccharides.

MAPPING

Misago et al. (1995) demonstrated that the gene encoding Golgi
alpha-mannosidase II (MAN2A1; 154582) maps to chromosome 5q21-q22.
However, Gasparini et al. (1997) excluded linkage to this and 2 other
candidate genes in CDAN type II. They performed a genomewide linkage
search in 12 southern Italian families, including 1 consanguineous
pedigree. Positive lod scores were obtained with 7 markers on chromosome
20q. A lod score of 4.73 at theta = 0.0 was obtained with D20S863. The
HOMOG program demonstrated genetic homogeneity. Linkage disequilibrium
studies showed a strong association between 1 allele of D20S863 and the
disorder, suggesting that a major mutation arose from a common ancestor.
In the full report, Gasparini et al. (1997) stated the cytogenetic
location of the CDA II gene to be 20q11.2. A maximum 2-point lod score
of 5.4 at a recombination fraction of 0.00 was obtained with marker
D20S863. Strong evidence of allelic association with the disease was
detected with the same marker.

Schwarz et al. (2009) studied 5 consanguineous families with CDAN type
II using genomewide SNP analysis to screen for homozygous chromosomal
regions. They identified a single homozygous region on chromosome
20p12.1-p11.23. They noted that the CDAN2 locus had originally been
mapped to 20q11.2; however, more current contig builds have relocated
the markers with the highest CDAN2 lod scores to the minimal
homozygosity region on chromosome 20p11.

- Exclusion Studies

Fukuda et al. (1992) presented biochemical data suggesting that CDA type
II is due to a deficiency of either N-acetylglucoaminyltransferase II or
alpha-mannosidase II. However, linkage analysis by Iolascon et al.
(1997), which placed the CDAN2 gene on 20q11.2, excluded the genes
encoding these proteins.

The retsina (ret) phenotype in zebrafish results from mutation in the
gene encoding the erythroid anion exchange protein-1 (AE1; 109270). The
high number of binucleated erythroblasts, the presence of 'double
membranes,' and the reduction in posttranslational glycosylation of AE1
observed in the ret fish are reminiscent of human CDA II. Perrotta et
al. (2003) excluded the AE1 gene as the cause of CDA II in humans. This
was not an unlikely finding, since AE1 maps to chromosome 17 and most
CDA II families show linkage to 20q. Furthermore, complete inactivation
of AE1 in mice and cattle causes severe hemolytic anemia, but not the
CDA II phenotype. In humans, absence of erythroid AE1 causes severe
hereditary spherocytosis (109270), but not CDA II.

HETEROGENEITY

Genetic heterogeneity in type II congenital dyserythropoietic anemia was
demonstrated by Iolascon et al. (1998) who found 2 unrelated families in
which CDA II was not linked to the CDAN2 locus on chromosome 20q11. The
first family came from a little town on the Ionian Sea in southern
Italy. Three of the grandparents of the affected individuals had the
same family name. The propositus was born in 1982; at 3 days of age,
severe icterus required exchange transfusion. Severe thrombocytopenia
was observed. In later years, anemia seldom required transfusions and
the platelet count was always low. Bone marrow studies and electron
microscopy showed the characteristic features of CDA II associated with
severe reduction of megakaryocytes, which did not show double membranes.
The second family came from Lecce, a province of southern Italy, and had
2 affected sibs.

MOLECULAR GENETICS

In affected individuals from 23 families with congenital
dyserythropoietic anemia type II (CDA II; 224100), Schwarz et al. (2009)
identified 18 different mutations and 1 deletion in the SEC23B gene
(see, e.g., 610512.0001-610512.0005). All mutations were in the
homozygous or compound heterozygous state, consistent with autosomal
recessive inheritance.

Bianchi et al. (2009) identified 12 different mutations in the SEC23B
gene (see, e.g., R217X, 610512.0006) in 13 patients from 10 unrelated
families with CDAN2. The most common mutations were E109K (610512.0001)
and R14W (610512.0002). Most of the patients were Italian.

NOMENCLATURE

Crookston and Crookston (1972) suggested the designation HEMPAS, an
acronym for 'hereditary erythroblastic multinuclearity with positive
acidified-serum test' (also called Ham test). This appears to be the
commonest form of inherited dyserythropoietic anemia. It is called type
II hereditary dyserythropoietic anemia in the classification of Wendt
and Heimpel (1967). (See 105600 and 224120 for 2 distinct forms of CDA
that do not have a positive acidified-serum test.)

ANIMAL MODEL

Schwarz et al. (2009) found that knockdown of the Sec23b gene in
zebrafish embryos led to a pronounced reduction of the lower jaw on day
3 postfertilization. Erythrocytes derived from the Sec23b-silenced
zebrafish showed an increase in immature, binucleated erythrocytes
compared to wildtype. However, the complete human phenotype was not
replicated, probably due to early lethality in the zebrafish. There was
no evidence of N-linked hypoglycosylation or duplication of rough
endoplasmic reticulum.

*FIELD* SA
Dewar and Lowenthal (1980); Roberts et al. (1962); Seip et al. (1975);
Verwilghen et al. (1973); Weiss et al. (1975)
*FIELD* RF
1. Baines, A. J.; Banga, J. P. S.; Gratzer, W. B.; Linch, D. C.; Huehns,
E. R.: Red cell membrane protein anomalies in congenital dyserythropoietic
anaemia, type II (HEMPAS). Brit. J. Haemat. 50: 563-574, 1982.

2. Bianchi, P.; Fermo, E.; Vercellati, C.; Boschetti, C.; Barcellini,
W.; Iurlo, A.; Marcello, A. P.; Righetti, P. G.; Zanella, A.: Congenital
dyserythropoietic anemia type II (CDAII) is caused by mutations in
the SEC23B gene. Hum. Mutat. 30: 1292-1298, 2009.

3. Crookston, J. H.; Crookston, M. C.: Hereditary anemia with multinuclear
erythroblasts ('HEMPAS'). Birth Defects Orig. Art. Ser. VIII(3):
15-19, 1972.

4. Crookston, J. H.; Crookston, M. C.; Burnie, K. L.; Francombe, W.
H.; Dacie, J. V.; Davis, J. A.; Lewis, S. M.: Hereditary erythroblastic
multinuclearity associated with a positive acidified-serum test: a
type of congenital dyserythropoietic anaemia. Brit. J. Haemat. 17:
11-26, 1969.

5. de Lozzio, C. B.; Valencia, J. I.; Acame, E.: Chromosomal study
in erythroblastic endopolyploidy. Lancet 279: 1004-1005, 1962. Note:
Originally Volume I.

6. Dewar, C. L.; Lowenthal, R. M.: Ultrastructural studies of an
unusual variant of congenital dyserythropoietic anaemia type II. Acta
Haemat. 64: 53-57, 1980.

7. Enquist, R. W.; Gockerman, J. P.; Jenis, E. H.; Warkel, R. L.;
Dillon, D. E.: Type II congenital dyserythropoietic anemia. Ann.
Intern. Med. 77: 371-376, 1972.

8. Fukuda, M. N.; Dell, A.; Scartezzini, P.: Primary defect of congenital
dyserythropoietic anaemia type II: failure in glycosylation of erythrocyte
lactosaminoglycan proteins caused by lowered N-acetylglucosaminyltransferase
II. J. Biol. Chem. 262: 7195-7206, 1987.

9. Fukuda, M. N.; Gaetani, G. F.; Izzo, P.; Scartezzini, P.; Dell,
A.: Incompletely processed N-glycans of serum glycoproteins in congenital
dyserythropoietic anaemia type II (HEMPAS). Brit. J. Haemat. 82:
745-752, 1992.

10. Fukuda, M. N.; Masri, K.A.; Dell, A.; Luzzatto, L.; Moremen, K.
W.: Incomplete synthesis of N-glycans in congenital dyserythropoietic
anemia type II caused by a defect in the gene encoding alpha-mannosidase
II. Proc. Nat. Acad. Sci. 87: 7443-7447, 1990.

11. Fukuda, M. N.; Papayannopoulou, T.; Gordon-Smith, E. C.; Rochant,
H.; Testa, U.: Defect in glycosylation of erythrocyte membrane proteins
in congenital dyserythropoietic anaemia type II (HEMPAS). Brit. J.
Haemat. 56: 55-68, 1984.

12. Gasparini, P.; del Giudice, E. M.; Delaunay, J.; Totaro, A.; Granatiero,
M.; Melchionda, S.; Zelante, L.; Iolascon, A.: Localization of the
congenital dyserythropoietic anemia II locus to chromosome 20q11.2
by genomewide search. Am. J. Hum. Genet. 61: 1112-1116, 1997.

13. Gasparini, P.; Miraglia del Giudice, E.; Delaunay, J.; Totaro,
A.; Granatiero, M.; Melchionda, S.; Zelante, L.; Iolascon, A.: Mapping
of congenital dyserythropoietic anemia II (CDAII) locus on the long
arm of chromosome 20 by genome wide search. (Abstract) Am. J. Hum.
Genet. 61 (suppl.): A276 only, 1997.

14. Iolascon, A.; Delaunay, J.; Wickramasinghe, S. N.; Perrotta, S.;
Gigante, M.; Camaschella, C.: Natural history of congenital dyserythropoietic
anemia type II. Blood 98: 1258-1260, 2001.

15. Iolascon, A.; De Mattia, D.; Perrotta, S.; Carella, M.; Gasparini,
P.; Deliliers, G. L.: Genetic heterogeneity of congenital dyserythropoietic
anemia type II. (Letter) Blood 92: 2593-2594, 1998.

16. Iolascon, A.; Miraglia del Giudice, E.; Perrotta, S.; Granatiero,
M.; Zelante, L.; Gasparini, P.: Exclusion of three candidate genes
as determinants of congenital dyserythropoietic anemia type II (CDA-II). Blood 90:
4197-4200, 1997.

17. Lowenthal, R. M.; Marsden, K. A.; Dewar, C. L.; Thompson, G. R.
: Congenital dyserythropoietic anaemia (CDA) with severe gout, rare
Kell phenotype and erythrocyte, granulocyte and platelet membrane
reduplication: a new variant of CDA type II. Brit. J. Haemat. 44:
211-220, 1980.

18. Misago, M.; Liao, Y.-F.; Kudo, S.; Eto, S.; Mattei, M.-G.; Moremen,
K. W.; Fukuda, M. N.: Molecular cloning and expression of cDNAs encoding
human alpha-mannosidase II and a previously unrecognized alpha-mannosidase
II(X) isozyme. Proc. Nat. Acad. Sci. 92: 11766-11770, 1995.

19. Perrotta, S.; del Guidice, E. M.; Carbone, R.; Servedio, V.; Schettini,
F., Jr.; Nobili, B.; Iolascon, A.: Gilbert's syndrome accounts for
the phenotypic variability of congenital dyserythropoietic anemia
type II (CDA-II). J. Pediat. 136: 556-559, 2000.

20. Perrotta, S.; Luzzatto, L.; Carella, M.; Iolascon, A.: Congenital
dyserythropoietic anemia type II in human patients is not due to mutations
in the erythroid anion exchanger 1. (Letter) Blood 102: 2704-2705,
2003.

21. Roberts, P. D.; Wallis, P. G.; Jackson, A. D. M.: Haemolytic
anaemia with multinucleated normoblasts in the marrow. (Letter) Lancet 279:
1186, 1962. Note: Originally Volume I.

22. Schwarz, K.; Iolascon, A.; Verissimo, F.; Trede, N. S.; Horsley,
W.; Chen, W.; Paw, B. H.; Hopfner, K.-P.; Holzmann, K.; Russo, R.;
Esposito, M. R.; Spano, D.; and 10 others: Mutations affecting
the secretory COPII coat component SEC23B cause congenital dyserythropoietic
anemia type II. Nature Genet. 41: 936-940, 2009.

23. Seip, M.; Skrede, S.; Bjerve, K. S.; Hovig, T.; Gaarder, P. I.
: Congenital dyserythropoietic anaemia with features of both type
I and type II. Scand. J. Haemat. 15: 272-286, 1975.

24. Verwilghen, R. L.; Lewis, S. M.; Dacie, J. V.; Crookston, J. H.;
Crookston, M. C.: HEMPAS: congenital dyserythropoietic anaemia (type
II). Quart. J. Med. 42: 257-278, 1973.

25. Verwilghen, R. L.; Verhaegen, H.; Waumans, P.; Beert, J.: Ineffective
erythropoiesis with morphologically abnormal erythroblasts and unconjugated
hyperbilirubinaemia. Brit. J. Haemat. 17: 27-33, 1969.

26. Weiss, S.; Gafter, U.; van der Lyn, E.; Djaldetti, M.: Congenital
dyserythropoietic anaemia with peculiar nuclear abnormality. Scand.
J. Haemat. 15: 261-271, 1975.

27. Wendt, F.; Heimpel, H.: Kongenitale dyserythropoietische Anamie
bei einem zweieiigen Zwillingspaar. Med. Klin. 62: 172-177, 1967.

*FIELD* CS
INHERITANCE:
Autosomal recessive

ABDOMEN:
[Liver];
Jaundice;
[Biliary tract];
Cholelithiasis;
[Spleen];
Splenomegaly

SKIN, NAILS, HAIR:
[Skin];
Jaundice

HEMATOLOGY:
Anemia;
Ineffective erythropoiesis;
Hemolysis;
Erythroblast morphologic abnormalities;
Multinucleated erythroblasts;
Increased reticulocytes;
Osmotic fragility of red blood cells;
Hypoglycosylation of red blood cell membranes

LABORATORY ABNORMALITIES:
Increased serum unconjugated bilirubin

MISCELLANEOUS:
Variable age at diagnosis

MOLECULAR BASIS:
Caused by mutation in the homolog of the S. cerevisiae SEC23 gene
B (SEC23B, 610512.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 10/12/2009

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 01/14/2010
ckniffin: 10/12/2009

*FIELD* CN
Cassandra L. Kniffin - updated: 10/12/2009
Cassandra L. Kniffin - updated: 8/10/2009
Victor A. McKusick - updated: 11/26/2003
Victor A. McKusick - updated: 11/9/2001
Deborah L. Stone - updated: 10/4/2001
Victor A. McKusick - updated: 11/13/1998
Victor A. McKusick - updated: 5/15/1998
Victor A. McKusick - updated: 11/26/1997
Victor A. McKusick - updated: 10/22/1997

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
ckniffin: 02/10/2014
carol: 1/24/2014
carol: 9/9/2013
ckniffin: 12/21/2010
wwang: 11/23/2009
ckniffin: 10/12/2009
wwang: 8/11/2009
ckniffin: 8/10/2009
carol: 2/26/2009
terry: 2/24/2009
alopez: 3/18/2004
tkritzer: 12/3/2003
terry: 11/26/2003
cwells: 11/7/2003
carol: 11/28/2001
terry: 11/9/2001
carol: 10/4/2001
carol: 11/16/2000
carol: 2/15/1999
carol: 11/13/1998
terry: 11/13/1998
dholmes: 7/22/1998
dholmes: 7/2/1998
alopez: 6/8/1998
alopez: 6/3/1998
terry: 5/15/1998
mark: 12/9/1997
terry: 12/3/1997
terry: 11/26/1997
terry: 10/28/1997
jenny: 10/24/1997
terry: 10/22/1997
terry: 1/6/1997
mark: 1/19/1996
joanna: 1/17/1996
joanna: 1/6/1996
jason: 7/18/1994
davew: 7/11/1994
mimadm: 2/19/1994
carol: 9/29/1993
supermim: 3/16/1992
carol: 2/19/1991

MIM 610512
*RECORD*
*FIELD* NO
610512
*FIELD* TI
*610512 SEC23, S. CEREVISIAE, HOMOLOG OF, B; SEC23B
*FIELD* TX

DESCRIPTION

SEC23B is an essential component of coat protein complex II
read more(COPII)-coated vesicles that transport secretory proteins from the
endoplasmic reticulum (ER) to the Golgi complex. (Schwarz et al., 2009).

CLONING

By PCR of human B-cell and HepG2-cell cDNA libraries using primers based
on mouse Sec23, followed by screening a B-lymphocyte cDNA library,
Paccaud et al. (1996) cloned SEC23B. The deduced 767-amino acid protein
shares 47.6% identity with yeast Sec23 and 84.3% identity with human
SEC23A (610511). RNase protection assays detected variable levels of
SEC23B in all human tissues and cell lines examined. Schwarz et al.
(2009) stated that the SEC23B gene contains an N-terminal zinc finger,
Sec23/Sec24 trunk region, a beta sandwich, helical domain, and
C-terminal gelsolin-like region.

GENE FUNCTION

Paccaud et al. (1996) found that, unlike human SEC23A, human SEC23B
could not complement the growth defect in Sec23-null yeast.

Schwarz et al. (2009) demonstrated that SEC23B RNA expression was
increased relative to SEC23A expression during in vitro erythroid
differentiation of CD34+ blood cells in response to erythropoietin at
days 7 to 14. In seeded stable CD34+ cells, the relative expression
levels were equal. Silencing of SEC23B with shRNA resulted in an
increase in binucleated erythrocytes with twice the amount of DNA,
suggesting a defect in cytokinesis. The findings suggested that the cell
cycle of erythroid cells and their cytokinesis depend on a sufficient
level of SEC23B. Schwarz et al. (2009) hypothesized that a reduction in
SEC23B in erythroblasts may be cell-specific and not sufficiently
compensated for by SEC23A expression in these cells.

MAPPING

The International Radiation Hybrid Mapping Consortium mapped the SEC23B
gene to chromosome 20 (TMAP SHGC-31801).

MOLECULAR GENETICS

In affected individuals from 23 families with congenital
dyserythropoietic anemia type II (CDAN2; 224100), Schwarz et al. (2009)
identified 18 different mutations and 1 deletion in the SEC23B gene
(see, e.g., 610512.0001-612512.0005). All mutations were in the
homozygous or compound heterozygous state, consistent with autosomal
recessive inheritance.

Bianchi et al. (2009) identified 12 different mutations in the SEC23B
gene (see, e.g., R217X; 612512.0006) in 13 patients from 10 unrelated
families with CDAN2. The most common mutations were E109K (612512.0001)
and R14W (612512.0002). Most of the patients were Italian.

ANIMAL MODEL

Schwarz et al. (2009) found that knockdown of the Sec23b gene in
zebrafish embryos led to a pronounced reduction of the lower jaw on day
3 post fertilization. Erythrocytes derived from the Sec23b-silenced
zebrafish showed an increase in immature, binucleated erythrocytes
compared to wildtype. However, the complete human phenotype was not
replicated, probably due to early lethality in the zebrafish. There was
no evidence of N-linked hypoglycosylation or duplication of rough
endoplasmic reticulum.

*FIELD* AV
.0001
ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE II
SEC23B, GLU109LYS

In affected members of 7 unrelated families with congenital
dyserythropoietic anemia type II (CDAN2; 224100), Schwarz et al. (2009)
identified a homozygous 325G-A transition in exon 4 of the SEC23B gene,
resulting in a glu109-to-lys (E109K) substitution in the N-terminal zinc
finger domain. Two additional probands were compound heterozygous for
E109K and another pathogenic mutation. The mutation was not identified
in 237 healthy individuals. Haplotype analysis did not identify a
founder effect. In vitro functional expression studies showed that the
E109K protein was unstable, with less than 5% of protein detectable
compared to wildtype SEC23B.

Bianchi et al. (2009) identified a homozygous E109K mutation in 3
members of an Italian family with CDAN2 and in another unrelated Italian
patient with the disorder.

.0002
ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE II
SEC23B, ARG14TRP

In affected members of 10 unrelated families with congenital
dyserythropoietic anemia type II (CDAN2; 224100), Schwarz et al. (2009)
identified compound heterozygosity for 2 mutations in the SEC23B gene.
All families had a heterozygous 40C-T transition in exon 2, resulting in
an arg14-to-trp (R14W) substitution at the interface of the zinc finger
domain and SEC23B core fold. In vitro functional expression studies
showed that the R14W protein was unstable, with less than 5% of protein
detectable compared to wildtype SEC23B. Mutations found in compound
heterozygosity with R14W included a 1588C-T transition in exon 14,
resulting in an arg530-to-trp (R530W; 610512.0003) substitution; a
790C-T transition in exon 7, resulting in an arg264-to-ter (R264X;
610512.0004) substitution; and a 970C-T transition in exon 8, resulting
in an arg324-to-ter (R324X; 610512.0005) substitution.

Bianchi et al. (2009) identified the R14W mutation in compound
heterozygosity with another pathogenic SEC23B mutation (see, e.g.,
R217X; 610512.0006) in 6 patients from 5 unrelated families with CDAN2.
All of the patients were Italian, except for 1 who was Rumanian.

.0003
ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE II
SEC23B, ARG530TRP

See 610512.0002 and Schwarz et al. (2009).

.0004
ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE II
SEC23B, ARG264TER

See 610512.0002 and Schwarz et al. (2009).

.0005
ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE II
SEC23B, ARG324TER

See 610512.0002 and Schwarz et al. (2009).

.0006
ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE II
SEC23B, ARG217TER

In 2 Italian sibs with CDA type II (CDAN2; 224100), Bianchi et al.
(2009) identified compound heterozygosity for 2 mutations in the SEC23B
gene: a 649C-T transition in exon 6, resulting in an arg217-to-ter
(R217X) substitution, and the R14W mutation (610512.0002).

*FIELD* RF
1. Bianchi, P.; Fermo, E.; Vercellati, C.; Boschetti, C.; Barcellini,
W.; Iurlo, A.; Marcello, A. P.; Righetti, P. G.; Zanella, A.: Congenital
dyserythropoietic anemia type II (CDAII) is caused by mutations in
the SEC23B gene. Hum. Mutat. 30: 1292-1298, 2009.

2. Paccaud, J.-P.; Reith, W.; Carpentier, J.-L.; Ravazzola, M.; Amherdt,
M.; Schekman, R.; Orci, L.: Cloning and functional characterization
of mammalian homologues of the COPII component Sec23. Molec. Biol.
Cell 7: 1535-1546, 1996.

3. Schwarz, K.; Iolascon, A.; Verissimo, F.; Trede, N. S.; Horsley,
W.; Chen, W.; Paw, B. H.; Hopfner, K.-P.; Holzmann, K.; Russo, R.;
Esposito, M. R.; Spano, D.; and 10 others: Mutations affecting
the secretory COPII coat component SEC23B cause congenital dyserythropoietic
anemia type II. (Letter) Nature Genet. 41: 936-940, 2009.

*FIELD* CN
Cassandra L. Kniffin - updated: 10/12/2009
Cassandra L. Kniffin - updated: 8/10/2009

*FIELD* CD
Patricia A. Hartz: 10/20/2006

*FIELD* ED
carol: 02/11/2014
ckniffin: 2/10/2014
carol: 12/23/2009
wwang: 11/23/2009
ckniffin: 10/12/2009
wwang: 8/11/2009
ckniffin: 8/10/2009
alopez: 7/3/2007
terry: 6/29/2007
mgross: 10/20/2006

RBCC Red Blood Cell Collection

Full text data of SEC23B