RBCC

Full text data of SEC23A

SEC23A [Confidence: low (only semi-automatic identification from reviews)]
Protein transport protein Sec23A (SEC23-related protein A)

UniProt Q15436
ID SC23A_HUMAN Reviewed; 765 AA.
AC Q15436; B2R5P4; Q8NE16;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 06-MAR-2007, sequence version 2.
DT 22-JAN-2014, entry version 131.
DE RecName: Full=Protein transport protein Sec23A;
DE AltName: Full=SEC23-related protein A;
GN Name=SEC23A;
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 VAL-211.
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 MRNA], AND VARIANT VAL-211.
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S.,
RA Sun H., Du H., Pepin K., Artiguenave F., Robert C., Cruaud C.,
RA Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P.,
RA Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N.,
RA Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C.,
RA Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S.,
RA Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B.,
RA Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M.,
RA Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S.,
RA Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D.,
RA Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A.,
RA Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L.,
RA Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J.,
RA Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W.,
RA Quetier F., Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT VAL-211.
RC TISSUE=Testis;
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 INTERACTION WITH SEC16A.
RC TISSUE=Liver;
RX PubMed=17192411; DOI=10.1091/mbc.E06-08-0707;
RA Bhattacharyya D., Glick B.S.;
RT "Two mammalian Sec16 homologues have nonredundant functions in
RT endoplasmic reticulum (ER) export and transitional ER organization.";
RL Mol. Biol. Cell 18:839-849(2007).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-308, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [7]
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 [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT THR-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 [9]
RP STRUCTURE BY NMR OF 57-108.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the ZF-SEC23_SEC24 from human SEC23A.";
RL Submitted (OCT-2007) to the PDB data bank.
RN [10]
RP VARIANT CLSD LEU-382, AND CHARACTERIZATION OF VARIANT CLSD LEU-382.
RX PubMed=16980979; DOI=10.1038/ng1876;
RA Boyadjiev S.A., Fromme J.C., Ben J., Chong S.S., Nauta C., Hur D.J.,
RA Zhang G., Hamamoto S., Schekman R., Ravazzola M., Orci L., Eyaid W.;
RT "Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation
RT leading to abnormal endoplasmic-reticulum-to-Golgi trafficking.";
RL Nat. Genet. 38:1192-1197(2006).
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.
CC -!- SUBUNIT: COPII is composed of at least five proteins: the Sec23/24
CC complex, the Sec13/31 complex and Sar1. Interacts with SEC23IP.
CC Interacts with HTR4 (By similarity). Interacts with SLC6A4 (By
CC similarity). Interacts with SEC16A.
CC -!- INTERACTION:
CC Q00536:CDK16; NbExp=3; IntAct=EBI-81088, EBI-726261;
CC P53992:SEC24C; NbExp=5; IntAct=EBI-81088, EBI-81134;
CC -!- SUBCELLULAR LOCATION: Smooth endoplasmic reticulum membrane;
CC Peripheral membrane protein. Golgi apparatus membrane; Peripheral
CC membrane protein (Potential). Note=In the ribosome-free
CC transitional face of the ER and associated vesicles.
CC -!- DISEASE: Craniolenticulosutural dysplasia (CLSD) [MIM:607812]:
CC Autosomal recessive syndrome characterized by late-closing
CC fontanels, sutural cataracts, facial dysmorphisms and skeletal
CC defects. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the SEC23/SEC24 family. SEC23 subfamily.
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DR EMBL; X97064; CAA65774.1; -; mRNA.
DR EMBL; AK312259; BAG35191.1; -; mRNA.
DR EMBL; AL109628; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC036649; AAH36649.1; -; mRNA.
DR PIR; T09574; T09574.
DR RefSeq; NP_006355.2; NM_006364.2.
DR UniGene; Hs.272927; -.
DR PDB; 2NUP; X-ray; 2.80 A; A=1-765.
DR PDB; 2NUT; X-ray; 2.30 A; A=1-765.
DR PDB; 2YRC; NMR; -; A=57-108.
DR PDB; 2YRD; NMR; -; A=57-108.
DR PDB; 3EFO; X-ray; 2.70 A; A=1-765.
DR PDB; 3EG9; X-ray; 3.00 A; A=1-764.
DR PDB; 3EGD; X-ray; 2.70 A; A=1-764.
DR PDB; 3EGX; X-ray; 3.30 A; A=1-764.
DR PDBsum; 2NUP; -.
DR PDBsum; 2NUT; -.
DR PDBsum; 2YRC; -.
DR PDBsum; 2YRD; -.
DR PDBsum; 3EFO; -.
DR PDBsum; 3EG9; -.
DR PDBsum; 3EGD; -.
DR PDBsum; 3EGX; -.
DR ProteinModelPortal; Q15436; -.
DR SMR; Q15436; 3-762.
DR IntAct; Q15436; 26.
DR MINT; MINT-4998885; -.
DR STRING; 9606.ENSP00000306881; -.
DR PhosphoSite; Q15436; -.
DR DMDM; 143811354; -.
DR PaxDb; Q15436; -.
DR PRIDE; Q15436; -.
DR DNASU; 10484; -.
DR Ensembl; ENST00000307712; ENSP00000306881; ENSG00000100934.
DR GeneID; 10484; -.
DR KEGG; hsa:10484; -.
DR UCSC; uc001wup.1; human.
DR CTD; 10484; -.
DR GeneCards; GC14M039501; -.
DR H-InvDB; HIX0011611; -.
DR HGNC; HGNC:10701; SEC23A.
DR MIM; 607812; phenotype.
DR MIM; 610511; gene.
DR neXtProt; NX_Q15436; -.
DR Orphanet; 50814; Craniolenticulosutural dysplasia.
DR PharmGKB; PA35624; -.
DR eggNOG; COG5047; -.
DR HOGENOM; HOG000231690; -.
DR HOVERGEN; HBG055039; -.
DR InParanoid; Q15436; -.
DR KO; K14006; -.
DR OMA; NYTGGYM; -.
DR PhylomeDB; Q15436; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; SEC23A; human.
DR EvolutionaryTrace; Q15436; -.
DR GeneWiki; SEC23A; -.
DR GenomeRNAi; 10484; -.
DR NextBio; 39780; -.
DR PRO; PR:Q15436; -.
DR ArrayExpress; Q15436; -.
DR Bgee; Q15436; -.
DR CleanEx; HS_SEC23A; -.
DR Genevestigator; Q15436; -.
DR GO; GO:0030127; C:COPII vesicle coat; IEA:InterPro.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0012507; C:ER to Golgi transport vesicle membrane; TAS:Reactome.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0030868; C:smooth endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; TAS:Reactome.
DR GO; GO:0002474; P:antigen processing and presentation of peptide antigen via MHC class I; TAS:Reactome.
DR GO; GO:0048208; P:COPII vesicle coating; TAS:Reactome.
DR GO; GO:0006886; P:intracellular protein transport; IEA:InterPro.
DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome.
DR GO; GO:0018279; P:protein N-linked glycosylation via asparagine; TAS:Reactome.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
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 3D-structure; Acetylation; Complete proteome; Disease mutation;
KW Endoplasmic reticulum; ER-Golgi transport; Golgi apparatus; Membrane;
KW Phosphoprotein; Polymorphism; Protein transport; Reference proteome;
KW Transport.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 765 Protein transport protein Sec23A.
FT /FTId=PRO_0000205146.
FT MOD_RES 2 2 N-acetylthreonine.
FT MOD_RES 308 308 Phosphothreonine.
FT VARIANT 211 211 L -> V (in dbSNP:rs8018720).
FT /FTId=VAR_031029.
FT VARIANT 382 382 F -> L (in CLSD; loss of function
FT mutation; cargo proteins retained in the
FT endoplasmic reticulum).
FT /FTId=VAR_031030.
FT CONFLICT 623 623 L -> M (in Ref. 4; AAH36649).
FT HELIX 4 15
FT STRAND 16 24
FT HELIX 28 31
FT STRAND 39 42
FT TURN 64 66
FT STRAND 74 77
FT TURN 78 81
FT STRAND 82 84
FT STRAND 86 88
FT STRAND 91 93
FT HELIX 96 98
FT HELIX 102 105
FT HELIX 108 110
FT HELIX 112 114
FT STRAND 115 121
FT STRAND 130 136
FT HELIX 141 155
FT STRAND 163 179
FT TURN 181 183
FT STRAND 185 190
FT HELIX 198 204
FT STRAND 228 232
FT HELIX 233 246
FT HELIX 264 278
FT STRAND 285 292
FT STRAND 296 299
FT HELIX 313 317
FT HELIX 324 341
FT STRAND 344 350
FT HELIX 357 360
FT HELIX 362 366
FT STRAND 371 375
FT STRAND 377 379
FT HELIX 380 388
FT STRAND 401 410
FT STRAND 414 422
FT STRAND 431 433
FT STRAND 439 442
FT STRAND 444 451
FT STRAND 457 463
FT STRAND 467 469
FT STRAND 477 487
FT STRAND 488 490
FT STRAND 492 501
FT HELIX 506 508
FT HELIX 509 515
FT HELIX 519 534
FT HELIX 542 557
FT STRAND 558 561
FT HELIX 565 567
FT TURN 572 576
FT HELIX 577 586
FT TURN 588 590
FT HELIX 592 594
FT HELIX 597 607
FT HELIX 612 619
FT STRAND 622 626
FT STRAND 628 631
FT STRAND 633 635
FT HELIX 639 641
FT STRAND 647 651
FT STRAND 653 660
FT HELIX 662 670
FT TURN 671 674
FT HELIX 676 678
FT HELIX 679 698
FT STRAND 699 701
FT STRAND 704 709
FT TURN 713 715
FT HELIX 716 721
FT HELIX 749 760
SQ SEQUENCE 765 AA; 86161 MW; 128DF9964B253313 CRC64;
MTTYLEFIQQ NEERDGVRFS WNVWPSSRLE ATRMVVPVAA LFTPLKERPD LPPIQYEPVL
CSRTTCRAVL NPLCQVDYRA KLWACNFCYQ RNQFPPSYAG ISELNQPAEL LPQFSSIEYV
VLRGPQMPLI FLYVVDTCME DEDLQALKES MQMSLSLLPP TALVGLITFG RMVQVHELGC
EGISKSYVFR GTKDLSAKQL QEMLGLSKVP LTQATRGPQV QQPPPSNRFL QPVQKIDMNL
TDLLGELQRD PWPVPQGKRP LRSSGVALSI AVGLLECTFP NTGARIMMFI GGPATQGPGM
VVGDELKTPI RSWHDIDKDN AKYVKKGTKH FEALANRAAT TGHVIDIYAC ALDQTGLLEM
KCCPNLTGGY MVMGDSFNTS LFKQTFQRVF TKDMHGQFKM GFGGTLEIKT SREIKISGAI
GPCVSLNSKG PCVSENEIGT GGTCQWKICG LSPTTTLAIY FEVVNQHNAP IPQGGRGAIQ
FVTQYQHSSG QRRIRVTTIA RNWADAQTQI QNIAASFDQE AAAILMARLA IYRAETEEGP
DVLRWLDRQL IRLCQKFGEY HKDDPSSFRF SETFSLYPQF MFHLRRSSFL QVFNNSPDES
SYYRHHFMRQ DLTQSLIMIQ PILYAYSFSG PPEPVLLDSS SILADRILLM DTFFQILIYH
GETIAQWRKS GYQDMPEYEN FRHLLQAPVD DAQEILHSRF PMPRYIDTEH GGSQARFLLS
KVNPSQTHNN MYAWGQESGA PILTDDVSLQ VFMDHLKKLA VSSAA
//

MIM 607812
*RECORD*
*FIELD* NO
607812
*FIELD* TI
#607812 CRANIOLENTICULOSUTURAL DYSPLASIA; CLSD
;;BOYADJIEV-JABS SYNDROME
*FIELD* TX
read moreA number sign (#) is used with this entry because of evidence that
craniolenticulosutural dysplasia (CSLD) can be caused by homozygous
mutation in the SEC23A gene (610511) on chromosome 14q21.

DESCRIPTION

Craniolenticulosutural dysplasia is an autosomal recessive disorder
characterized by facial dysmorphism, late-closing fontanels, cataract,
and skeletal defects (summary by Boyadjiev et al., 2011).

CLINICAL FEATURES

Boyadjiev et al. (2003) suggested the designation craniolenticulosutural
dysplasia (CLSD) for a dysmorphic syndrome in 5 males and 1 female in an
inbred Saudi Arabian family. The craniofacial features included wide
open calvarial sutures with large and late-closing anterior fontanels,
frontal bossing, hyperpigmentation with capillary hemangioma of the
forehead, significant hypertelorism, and a broad and prominent nose. All
affected individuals had Y-shaped sutural cataracts diagnosed by 1 to 2
years of age.

Boyadjiev et al. (2011) reported a 4.5-year-old boy with CLSD who had a
characteristic facial appearance as well as clinical and skeletal
features similar to those of the original patients described by
Boyadjiev et al. (2003). Facial features common to all CLSD patients
included high and prominent forehead with increased vascular markings in
the area of the open anterior fontanel, similar shape of the eyebrows,
obvious hypertelorism, wide and prominent nasal ridge, and anteverted
nares, with lateral skull x-rays documenting large and hypomineralized
calvaria in the area of the anterior fontanel. However, the eye
phenotypes differed, with esotropia, bilateral optic atrophy, and
double-ring sign of the lens present in the new case, but no cataract
detected by 4.5 years of age. Other previously undescribed features
included macrocephaly, anterior frenulum linguae requiring frenulectomy,
bifid uvula, cleft palate, gastroesophageal reflux with postnatal
failure to thrive, valvular pulmonic stenosis, and osteopenia.

MAPPING

By a genomewide scan, Boyadjiev et al. (2003) found linkage of
craniolenticulosutural dysplasia in the Saudi Arabian family to
chromosome 14q13-q21; the maximum 2-point lod score, assuming recessive
inheritance, was 4.58 at theta = 0.0 with marker GATA126A04. Haplotype
analysis narrowed the disease locus to a region of approximately 7.26
Mb.

MOLECULAR GENETICS

In affected members of a Saudi Arabian family with CLSD, Boyadjiev et
al. (2006) identified a homozygous missense mutation in the SEC23A gene
(F382L; 610511.0001). SEC23A is an essential component of the
COPII-coated vesicles that transport secretory proteins from the
endoplasmic reticulum to the Golgi complex. In fibroblasts from
individuals affected with CLSD, a gross dilatation of the endoplasmic
reticulum was demonstrated by electron microscopy and
immunofluorescence. These cells also exhibited cytoplasmic
mislocalization of SEC31 (see 610257).

In a 4.5-year-old boy with CLSD, Boyadjiev et al. (2011) identified
heterozygosity for a paternally inherited missense mutation in the
SEC23A gene (M702V; 610511.0002); no mutations were identified in the
coding region or 5-prime or 3-prime UTR of maternal SEC23A, and SNP and
RT-PCR analysis excluded deletion of the maternal allele. Cultured skin
fibroblasts from the patient showed a severe secretion defect of
collagen with enlarged endoplasmic reticulum (ER); milder collagen
secretion defects and ER distention were present in fibroblasts from the
clinically unaffected father, indicating that an additional mutation was
present in the proband. Boyadjiev et al. (2011) suggested that digenic
inheritance might be involved in CLSD; RT-PCR DNA sequencing of the
SEC23B (610512), SEC31A, and SEC13 (600152) genes revealed no mutations.

- Exclusion Studies

Boyadjiev et al. (2003) performed sequence analysis of the PAX9 gene
(167416) in members of the Saudi Arabian family with CLSD and found no
mutations.

*FIELD* RF
1. Boyadjiev, S. A.; Fromme, J. C.; Ben, J.; Chong, S. S.; Nauta,
C.; Hur, D. J.; Zhang, G.; Hamamoto, S.; Schekman, R.; Ravazzola,
M.; Orci, L.; Eyaid, W.: Cranio-lenticulo-sutural dysplasia is caused
by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi
trafficking. Nature Genet. 38: 1192-1197, 2006.

2. Boyadjiev, S. A.; Justice, C. M.; Eyaid, W.; McKusick, V. A.; Lachman,
R. S.; Chowdry, A. B.; Jabak, M.; Zwaan, J.; Wilson, A. F.; Jabs,
E. W.: A novel dysmorphic syndrome with open calvarial sutures and
sutural cataracts maps to chromosome 14q13-q21. Hum. Genet. 113:
1-9, 2003.

3. Boyadjiev, S. A.; Kim, S.-D.; Hata, A.; Haldeman-Englert, C.; Zackai,
E. H.; Naydenov, C.; Hamamoto, S.; Schekman, R. W.; Kim, J.: Cranio-lenticulo-sutural
dysplasia associated with defects in collagen secretion. Clin. Genet. 80:
169-176, 2011.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Height];
Short stature;
[Other];
Failure to thrive, postnatal, due to gastroesophageal reflux (in some
patients)

HEAD AND NECK:
[Head];
Large anterior fontanel;
Delayed closure anterior fontanel;
Macrocephaly;
[Face];
Frontal bossing;
Forehead hyperpigmentation;
Prominent supraorbital ridge;
Midface hypoplasia;
Long, smooth philtrum;
[Eyes];
Hypertelorism;
Y-shaped sutural cataract (in some patients);
Punctate lenticular opacities;
Esotropia (in some patients);
Optic atrophy, bilateral (in some patients);
Double-ring sign of lens (in some patients);
[Nose];
Broad nasal bridge;
Anteverted nares;
[Mouth];
Wide mouth;
Thin upper lip;
Bifid uvula (in some patients);
Cleft palate (in some patients);
[Teeth];
Delayed eruption;
Dental caries (secondary teeth);
Hypoplastic teeth (secondary teeth)

CARDIOVASCULAR:
[Cardiac];
Valvular pulmonic stenosis (in some patients)

ABDOMEN:
[Gastrointestinal];
Gastroesophageal reflux (in some patients)

GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism

SKELETAL:
Joint laxity;
Osteopenia (in some patients);
[Skull];
Ossification defects;
[Spine];
Scoliosis;
Posterior wedging of vertebral bodies;
[Pelvis];
High, narrow iliac wings;
[Feet];
Flat feet

SKIN, NAILS, HAIR:
[Skin];
Hyperpigmentation (forehead);
Capillary hemangioma (forehead);
[Hair];
Coarse hair;
Brittle hair;
Sparse hair

MOLECULAR BASIS:
Caused by mutation in the human homolog A of the S. cerevisiae SEC23
gene (SEC23A, 610511.0001)

*FIELD* CN
Marla J. F. O'Neill - updated: 06/04/2013

*FIELD* CD
Kelly A. Przylepa: 11/29/2006

*FIELD* ED
joanna: 06/04/2013
joanna: 2/4/2011
joanna: 9/19/2007
joanna: 9/11/2007
alopez: 11/1/2006

*FIELD* CN
Marla J. F. O'Neill - updated: 02/11/2013
Victor A. McKusick - updated: 10/26/2006

*FIELD* CD
Victor A. McKusick: 5/21/2003

*FIELD* ED
carol: 02/11/2013
carol: 3/27/2012
alopez: 11/1/2006
terry: 10/26/2006
carol: 2/3/2006
joanna: 3/19/2004
carol: 6/6/2003
carol: 6/2/2003
tkritzer: 5/28/2003

MIM 610511
*RECORD*
*FIELD* NO
610511
*FIELD* TI
*610511 SEC23, S. CEREVISIAE, HOMOLOG OF, A; SEC23A
*FIELD* TX

DESCRIPTION

SEC23A 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. Formation of the COPII
complex is initiated when the small GTPase SAR1 (see SAR1B; 607690)
becomes anchored to the cytosolic surface of the ER, which requires
GDP/GTP exchange by the integral membrane glycoprotein SEC12. Activated
SAR1 directly binds the SEC23-SEC24 (see SEC24A; 607183) complex, a
heterodimer required for recognition of cargo proteins in the membrane.
Cargo molecules tethered to SAR1 and SEC23-SEC24 are coated by the SEC13
(see SEC13L1; 600152)-SEC31 (see SEC31L1; 610257) complex, forming buds
and vesicles destined for the Golgi apparatus. SEC23A also functions as
a SAR1-specific GTPase-activating protein (GAP) that hydrolyzes the GTP
bound to SAR1, which in turn triggers uncoating of vesicles after
budding (summary by Boyadjiev et al., 2006).

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 SEC23A. The deduced 765-amino acid protein
shares 47.3% identity with yeast Sec23 and 84.3% identity with human
SEC23B (610512). RNase protection assays detected variable levels of
SEC23A in all human tissues and cell lines examined. Western blot
analysis revealed an 85-kD SEC23A protein in HepG2 cells and in mouse
and rat tissues. SEC23A partitioned equally between cytosol and
membranes in HepG2 cells. Gel filtration of HepG2 cytosol showed that
SEC23A associated with protein complexes of 350 and more than 2,000 kD.
Immunocytochemical analysis localized SEC23A in a punctate distribution
at the periphery of the nucleus, and immunoelectron microscopy of HepG2
cells and rat pancreatic acinar cells showed SEC23A restricted to the
tubular extensions of the transitional endoplasmic reticulum and its
associated vesicles.

MAPPING

The International Radiation Hybrid Mapping Consortium mapped the SEC23A
gene to chromosome 14 (TMAP RH78878).

GENE FUNCTION

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

Cai et al. (2007) reported that in yeast and mammalian cells the
tethering complex TRAPPI binds to the coat subunit SEC23. This event
requires the BET3 subunit (TRAPPC3; 610955). In vitro studies
demonstrated that the interaction between SEC23 and BET3 targets TRAPPI
to COPII vesicles to mediate vesicle tethering. Cai et al. (2007)
proposed that the binding of TRAPPI to SEC23 marks a coated vesicle for
fusion with another COPII vesicle or the Golgi apparatus. An implication
of these findings is that the intracellular destination of a transport
vesicle may be determined in part by its coat and its associated cargo.

Lord et al. (2011) used a yeast transport assay to demonstrate that an
ER-derived vesicle retains its coat until it reaches the Golgi. A
Golgi-associated kinase, Hrr25p, which is a CKI-delta (600864) ortholog,
then phosphorylates the Sec23p/Sec24p complex. Coat phosphorylation and
dephosphorylation are needed for vesicle fusion and budding,
respectively. Additionally, Lord et al. (2011) showed that Sec23p
interacts in a sequential manner with different binding partners,
including TRAPPI and Hrr25p, to ensure the directionality of ER-Golgi
traffic and prevent the backfusion of a COPII vesicle with the ER. Lord
et al. (2011) stated that these events are conserved in mammalian cells.

MOLECULAR GENETICS

Craniolenticulosutural dysplasia (CLSD; 607812) is an autosomal
recessive syndrome characterized by late-closing fontanels, sutural
cataracts, facial dysmorphism, and skeletal defects, mapped to 14q13-q21
(Boyadjiev et al., 2003). Boyadjiev et al. (2006) identified a
phe382-to-leu (F382L) mutation in the SEC23A gene (610511.0001) in all 6
individuals with CLSD examined. Electron microscopy and
immunofluorescence showed gross dilatation of the endoplasmic reticulum
in fibroblasts from individuals with CLSD. These cells also exhibited
cytoplasmic mislocalization of SEC31. Liposome-binding assays and
cell-free vesicle budding assays showed that SEC23A with the F382L
substitution could bind SAR1B and SEC24D (607186) and could bind
membranes, but it was defective in its function in vesicle budding. A
phenotype reminiscent of CLSD was observed in zebrafish embryos injected
with Sec23a-blocking morpholinos. The observations of Boyadjiev et al.
(2006) suggested that disrupted endoplasmic reticulum export of
secretory proteins required for normal morphogenesis accounts for CLSD.

Using wildtype SEC23A and SEC23A containing the F382L mutation
(SEC23A-F382L) for in vitro and in vivo assays, Fromme et al. (2007)
demonstrated that SEC23A had an early role in formation of COPII
coat-containing vesicles at ER exit sites. SEC23A-F382L, in complex with
SEC24D, was defective in vesicle budding when paired with SAR1B. In
contrast, vesicle budding was present, though below wildtype levels,
when SEC23A-F382L was paired with SAR1A (607691). Both wildtype SEC23A
and SEC23A-F382L exhibited similarly modest rates of intrinsic GAP
activity toward SAR1A and SAR1B. However, stimulation of SEC23A GAP
activity by SEC13-SEC31A was significantly diminished by the F382L
substitution when paired with SAR1B, but not when paired with SAR1A.
SEC23A-F382L was unable to recruit the SEC13-SEC31 complex, and this
defect was partially mitigated when SAR1A was used with SEC23A-F382L
instead of SAR1B. The ER of CLSD patient fibroblasts homozygous for
F382L contained numerous tubular cargo-containing extensions devoid of
coat proteins, likely representing an intermediate step in COPII vesicle
formation. Fromme et al. (2007) concluded that the SAR1-SEC23-SEC24
prebudding complex is sufficient to form cargo-containing tubules in
vivo, whereas the SEC13-SEC31 complex is required for membrane fission.

In a 4.5-year-old boy with CLSD, Boyadjiev et al. (2011) identified a
paternally inherited missense mutation (M702V; 610511.0002) in the
SEC23A gene; no SEC23A mutation or deletion was detected in maternal
DNA. Cultured skin fibroblasts from the patient showed a severe
secretion defect of collagen with enlarged endoplasmic reticulum (ER);
milder collagen secretion defects and ER distention were observed in
paternal fibroblasts, indicating that an additional mutation was present
in the proband. Boyadjiev et al. (2011) suggested that digenic
inheritance might be involved in CLSD; RT-PCR DNA sequencing of the
SEC23B (610512), SEC31A (610257), and SEC13 (600152) genes revealed no
mutations.

ANIMAL MODEL

Zebrafish cranial skeleton develops within the first 3 days
postfertilization and is primarily built from cartilage elements that
later ossify. The zebrafish 'crusher' mutation was recovered during a
chemical mutagenesis screen for phenotypes affecting craniofacial
development (Neuhass et al., 1996). Lang et al. (2006) observed short
body length, small and malformed head skeleton, and absence of
cartilaginous ear capsules as its primary features. The neurocranium is
reduced to approximately 40% of the wildtype length and lacks
parachordal cartilages. Histologic analysis showed accumulation of
cartilage extracellular matrix (ECM) within developing chondrocytes,
indicating a defect in the secretory pathway. Using linkage analysis,
fine mapping of the crusher locus, and comparison of human and mouse
syntenic regions, Lang et al. (2006) identified sec23a as a likely
candidate gene. Sequencing of the sec23a coding region revealed a T-to-A
transversion at nucleotide 1287, leading to a premature stop codon
(L402X) in embryos homozygous for the crusher allele. Lang et al. (2006)
demonstrated that the paralogous gene sec23b (610512) is also an
essential component of the ECM secretory pathway in chondrocytes. In
contrast, knockdown of the COPI complex did not hinder craniofacial
morphogenesis. Lang et al. (2006) stated that crusher provided the first
vertebrate model system that links the biology of endoplasmic
reticulum-to-Golgi trafficking with a clinically relevant dysmorphology,
namely, craniolenticulosutural dysplasia syndrome.

*FIELD* AV
.0001
CRANIOLENTICULOSUTURAL DYSPLASIA
SEC23A, PHE382LEU

In all affected members of a consanguineous Saudi Arabian family of
Bedouin descent with craniolenticulosutural dysplasia (CLSD; 607812),
Boyadjiev et al. (2006) found a homozygous 1144T-C transition in exon 10
of the SEC23A gene, resulting in a phe382-to-leu (F382L) substitution.
The mutation, which involved a residue that is invariably conserved in
at least 10 species, was not present in 600 control chromosomes. On the
basis of the known biologic function of SEC23A, excessive accumulation
of secretory proteins in the rough endoplasmic reticulum of mutant
fibroblasts was predicted and was demonstrated by electron microscopy
and immunofluorescence.

Fromme et al. (2007) demonstrated that SEC23A-F382L, in complex with
SEC24D, was defective in vesicle budding when paired with SAR1B
(607690). In contrast, vesicle budding was present, although below
wildtype levels, when SEC23A-F382L was paired with SAR1A (607691). Both
wildtype SEC23A and SEC23A-F382L exhibited similarly modest rates of
intrinsic GAP activity toward SAR1A and SAR1B. However, stimulation of
SEC23A GAP activity by SEC13-SEC31A was significantly diminished by the
F382L substitution when paired with SAR1B, but not when paired with
SAR1A. SEC23A-F382L was unable to recruit the SEC13-SEC31 complex, and
this defect was partially mitigated when SAR1A was used with
SEC23A-F382L instead of SAR1B. The ER of CLSD patient fibroblasts
homozygous for F382L contained numerous tubular cargo-containing
extensions devoid of coat proteins, likely representing an intermediate
step in COPII vesicle formation.

.0002
CRANIOLENTICULOSUTURAL DYSPLASIA
SEC23A, MET702VAL

In a 4.5-year-old boy with craniolenticulosutural dysplasia (CLSD;
607812), Boyadjiev et al. (2011) identified heterozygosity for a
paternally inherited 2104A-G transition in the SEC23A gene, resulting in
a met702-to-val (M702V) substitution at a residue that is invariably
conserved in all higher eukaryotes. The M702V mutation was not present
in 372 Caucasian control chromosomes. No mutations were detected in the
coding region or 5-prime or 3-prime UTR of maternal SEC23A, and SNP and
RT-PCR analysis excluded deletion of the maternal allele. Cultured skin
fibroblasts from the patient showed a severe secretion defect of
collagen with enlarged endoplasmic reticulum (ER); milder collagen
secretion defects and ER distention were observed in fibroblasts from
the clinically unaffected father, indicating that an additional mutation
was present in the proband. Boyadjiev et al. (2011) suggested that
digenic inheritance might be involved in CLSD.

*FIELD* RF
1. Boyadjiev, S. A.; Fromme, J. C.; Ben, J.; Chong, S. S.; Nauta,
C.; Hur, D. J.; Zhang, G.; Hamamoto, S.; Schekman, R.; Ravazzola,
M.; Orci, L.; Eyaid, W.: Cranio-lenticulo-sutural dysplasia is caused
by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi
trafficking. Nature Genet. 38: 1192-1197, 2006.

2. Boyadjiev, S. A.; Justice, C. M.; Eyaid, W.; McKusick, V. A.; Lachman,
R. S.; Chowdry, A. B.; Jabak, M.; Zwaan, J.; Wilson, A. F.; Jabs,
E. W.: A novel dysmorphic syndrome with open calvarial sutures and
sutural cataracts maps to chromosome 14q13-q21. Hum. Genet. 113:
1-9, 2003.

3. Boyadjiev, S. A.; Kim, S.-D.; Hata, A.; Haldeman-Englert, C.; Zackai,
E. H.; Naydenov, C.; Hamamoto, S.; Schekman, R. W.; Kim, J.: Cranio-lenticulo-sutural
dysplasia associated with defects in collagen secretion. Clin. Genet. 80:
169-176, 2011.

4. Cai, H.; Yu, S.; Menon, S.; Cai, Y.; Lazarova, D.; Fu, C.; Reinisch,
K.; Hay, J. C.; Ferro-Novick, S.: TRAPPI tethers COPII vesicles by
binding the coat subunit Sec23. Nature 445: 941-944, 2007.

5. Fromme, J. C.; Ravazzola, M.; Hamamoto, S.; Al-Balwi, M.; Eyaid,
W.; Boyadjiev, S. A.; Cosson, P.; Schekman, R.; Orci, L.: The genetic
basis of a craniofacial disease provides insight into COPII coat assembly. Dev.
Cell 13: 623-634, 2007.

6. Lang, M. R.; Lapierre, L. A.; Frotscher, M.; Goldenring, J. R.;
Knapik, E. W.: Secretory COPII coat component Sec23a is essential
for craniofacial chondrocyte maturation. Nature Genet. 38: 1198-1203,
2006.

7. Lord, C.; Bhandari, D.; Menon, S.; Ghassemian, M.; Nycz, D.; Hay,
J.; Ghosh, P.; Ferro-Novick, S.: Sequential interactions with Sec23
control the direction of vesicle traffic. Nature 473: 181-186, 2011.

8. Neuhass, S. C.; Solnica-Krezel, L.; Schier, A. F.; Zwartkruis,
F.; Stemple, D. L.; Malicki, J.; Abdelilah, S.; Stainier, D. Y. R.;
Driever, W.: Mutations affecting craniofacial development in zebrafish. Development 123:
357-367, 1996.

9. 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.

*FIELD* CN
Marla J. F. O'Neill - updated: 02/11/2013
Ada Hamosh - updated: 5/23/2011
Matthew B. Gross - updated: 1/6/2009
Patricia A. Hartz - updated: 12/29/2008
Ada Hamosh - updated: 6/29/2007
Victor A. McKusick - updated: 10/26/2006

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

*FIELD* ED
carol: 02/11/2013
alopez: 5/24/2011
terry: 5/23/2011
mgross: 1/6/2009
terry: 12/29/2008
alopez: 7/18/2008
alopez: 11/6/2007
terry: 9/19/2007
alopez: 7/3/2007
terry: 6/29/2007
alopez: 11/1/2006
terry: 10/26/2006
mgross: 10/20/2006

RBCC Red Blood Cell Collection

Full text data of SEC23A