Alternative titles; symbols
HGNC Approved Gene Symbol: SEC23B
SNOMEDCT: 68870007;
Cytogenetic location: 20p11.23 Genomic coordinates (GRCh38): 20:18,507,548-18,561,415 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p11.23 | ?Cowden syndrome 7 | 616858 | Autosomal dominant | 3 |
| Dyserythropoietic anemia, congenital, type II | 224100 | Autosomal recessive | 3 |
SEC23B is an essential component of coat protein complex II (COPII)-coated vesicles that transport secretory proteins from the endoplasmic reticulum (ER) to the Golgi complex. (Schwarz et al., 2009).
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.
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.
Gross (2018) mapped the SEC23B gene to chromosome 20p11.23 based on an alignment of the SEC23B sequence (GenBank BC095404) with the genomic sequence (GRCh38).
Congenital Dyserythropoietic Anemia Type II
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.
Cowden Syndrome 7
In the proband from a large 5-generation family segregating autosomal dominant Cowden syndrome (CWS7; 616858) , Yehia et al. (2015) performed whole-exome sequencing and identified a heterozygous missense mutation in the SEC23B gene (V594G; 610512.0007); no variants were found in known Cowden syndrome-associated genes. Sanger sequencing confirmed segregation of V594G with disease in the family, and functional analysis demonstrated that the mutation causes endoplasmic reticulum (ER) stress-mediated cell-colony formation, survival, growth, and invasion, reflecting aspects of a cancer phenotype. Analysis of SEC23B in 96 patients with Cowden syndrome or a Cowden syndrome-like phenotype revealed 3 patients with mutations in SEC23B, including 2 unrelated women who were heterozygous for the same missense mutation (V164L; 610512.0008); however, this variant has been reclassified as a variant of unknown significance.
Sporadic Thyroid Cancer
Yehia et al. (2015) analyzed the spectrum and frequencies of SEC23B germline variants in cancer cases from The Cancer Genome Atlas (TCGA), including 494 cases of thyroid cancer, 222 cases of invasive breast cancer, and 156 cases of uterine corpus endometrioid cancer. They identified SEC23B germline variants in all 3 cancer types, with the highest frequency (4%) in thyroid cancer. The authors noted that there was also overrepresentation of unique SEC23B variants in thyroid cancer, and that these variants were predicted to be deleterious and absent from public databases, suggesting a functional role in sporadic thyroid cancer. The age-adjusted standardized incidence ratio of thyroid cancer in SEC23B variant-positive TCGA individuals was significantly higher than in the US general population (SIR = 242.6; p = 1 X 10(-11)). In addition, the median age at diagnosis of thyroid cancer was younger for SEC23B variant-positive individuals compared to the entire TCGA thyroid cancer cohort (36 vs 46 years; p = 0.025). Yehia et al. (2015) also performed an 'agnostic' search (irrespective of SEC23B mutation status) in the Catalogue of Somatic Mutations in Cancer and found that 625 (approximately 75%) of 828 cases of sporadic cancers of different types included overexpression of SEC23B transcripts, and that 84 (approximately 10%) showed high-level amplification (gain of copy number), suggesting that SEC23B might play a previously unappreciated role in carcinogenesis at large.
Reclassified Variants
The Y131H variant reported by Yehia et al. (2015) has been reclassified as a variant of unknown significance; see 610512.0008.
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.
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.
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 Romanian.
For discussion of the arg530-to-trp (R530W) mutation in the SEC23B gene that was found in compound heterozygous state in patients with congenital dyserythropoietic anemia type II (CDAN2; 224100) by Schwarz et al. (2009), see 610512.0002.
For discussion of the arg264-to-ter (R264X) mutation in the SEC23B gene that was found in compound heterozygous state in patients with congenital dyserythropoietic anemia type II (CDAN2; 224100) by Schwarz et al. (2009), see 610512.0002.
For discussion of the arg324-to-ter (R324X) mutation in the SEC23B gene that was found in compound heterozygous state in patients with congenital dyserythropoietic anemia type II (CDAN2; 224100) by Schwarz et al. (2009), see 610512.0002.
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).
In 5 affected members of a large 5-generation family (family 616) segregating autosomal dominant Cowden syndrome (CWS7; 616858), negative for mutation in known Cowden syndrome-associated genes, Yehia et al. (2015) identified heterozygosity for a c.1781T-G transversion (chr20.18,529,290, GRCh37) in the SEC23B gene, resulting in a val594-to-gly (V594G) substitution at a highly conserved residue between the alpha-N and alpha-M regions within the helical domain critical for binding to SAR1 (see SAR1A, 607691). The mutation was not found in 3 unaffected family members, and was not present in the dbSNP (build 137), 1000 Genomes Project, or NHLBI ESP6500 databases. Functional analysis in transfected HEK293T cells showed aberrant aggregation of SEC23B and significantly increased cell migration and upregulation of epithelial-to-mesenchymal transition genes with the V594G mutant compared to wildtype, suggesting a cancer-relevant effect. Immunoprecipitation studies revealed decreased interaction of SAR1A with the mutant protein. In transfected thyroid follicle epithelial cell lines, the mutant showed aberrant SEC23B aggregation compared to wildtype, but no differences in growth, viability, or migration ability were observed. However, Transwell invasion assays revealed a significantly greater (9-fold) increase in Matrigel invasion with the mutant compared to wildtype, and mutant cells showed increased activity of the matrix-digesting metalloproteinases MMP2 (120360) and MMP9 (120361), thus explaining the invasive potential of the cells.
This variant, formerly titled COWDEN SYNDROME 7, has been reclassified based on a review of the ExAC database by Hamosh (2018).
In 2 unrelated women (probands CCF02565 and CCF05664) with a Cowden-like syndrome (see 616858), Yehia et al. (2015) identified heterozygosity for a c.490G-T transversion in the SEC23B gene, resulting in a val164-to-leu (V164L; rs36023150) substitution at a highly conserved residue within the SEC23 trunk domain that forms the interface between SEC23 and SEC34 and also contacts SAR1 (see 607690). The T allele was present in 97 of 12,909 alleles in the NHLBI ESP6500 database (minor allele frequency = 0.0075). One of the affected women was diagnosed with follicular variant papillary thyroid cancer at age 52 years and also exhibited macrocephaly; the other woman was diagnosed with papillary thyroid cancer at age 45, and also had fibrocystic breast disease, atypical ductal hyperplasia, and ductal carcinoma in situ, as well as hemangioma and macrocephaly.
Hamosh (2018) found that the V164L variant was present in heterozygous state in 1,432 of 121,406 alleles and in 18 homozygotes, giving an allele frequency of 0.0118, in the ExAC database (July 11, 2018).
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. [PubMed: 19621418] [Full Text: https://doi.org/10.1002/humu.21077]
Gross, M. B. Personal Communication. Baltimore, Md. 7/16/2018.
Hamosh, A. Personal Communication. Baltimore, Md. 7/11/2018.
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. [PubMed: 8898360] [Full Text: https://doi.org/10.1091/mbc.7.10.1535]
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. [PubMed: 19561605] [Full Text: https://doi.org/10.1038/ng.405]
Yehia, L., Niazi, F., Ni, Y., Ngeow, J., Sankunny, M., Liu, Z., Wei, W., Mester, J. L., Keri, R. A., Zhang, B., Eng, C. Germline heterozygous variants in SEC23B are associated with Cowden syndrome and enriched in apparently sporadic thyroid cancer. Am. J. Hum. Genet. 97: 661-676, 2015. [PubMed: 26522472] [Full Text: https://doi.org/10.1016/j.ajhg.2015.10.001]