SEC23A rescues SEC23B-deficient congenital dyserythropoietic anemia type II

King, Richard A.; Lin, Zesen; Balbin-Cuesta, Ginette; Myers, Greggory; Friedman, Ann; Zhu, Guojing; McGee, Beth; Saunders, Thomas L.; Kurita, Ryo; Nakamura, Yukio; Engel, James Douglas; Reddy, Pavan; Khoriaty, Rami

doi:10.1126/sciadv.abj5293

Cited by 8 publications

(16 citation statements)

References 84 publications

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“…Indeed, we demonstrated that overexpression of SEC23A in SEC23B-silenced cells completely rescued the observed phenotype by re-activating BMP/SMADs signaling pathway and HAMP transcription. This is in agreement with a recent study on an erythroid SEC23B-deficient cellular model (HUDEP-2), whose CDA II phenotype was rescued by increased expression of SEC23A [48]. These results are highly relevant to suggest novel therapeutic approach for CDA II.…”

Section: Discussionsupporting

confidence: 92%

SEC23B Loss-of-Function Suppresses Hepcidin Expression by Impairing Glycosylation Pathway in Human Hepatic Cells

Rosato

Marra

D’Onofrio

et al. 2022

IJMS

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Biallelic pathogenic variants in the SEC23B gene cause congenital dyserythropoietic anemia type II (CDA II), a rare hereditary disorder hallmarked by ineffective erythropoiesis, hemolysis, erythroblast morphological abnormalities, and hypo-glycosylation of some red blood cell membrane proteins. Abnormalities in SEC23B, which encodes the homonymous cytoplasmic COPII (coat protein complex II) component, disturb the endoplasmic reticulum to Golgi trafficking and affect different glycosylation pathways. The most harmful complication of CDA II is the severe iron overload. Within our case series (28 CDA II patients), approximately 36% of them exhibit severe iron overload despite mild degree of anemia and slightly increased levels of ERFE (the only erythroid regulator of hepcidin suppression). Thus, we hypothesized a direct role of SEC23B loss-of-function in the pathomechanism of hepatic iron overload. We established a hepatic cell line, HuH7, stably silenced for SEC23B. In silenced cells, we observed significant alterations of the iron status, due to both the alteration in BMP/SMADs pathway effectors and a reduced capability to sense BMP6 stimulus. We demonstrated that the loss-of-function of SEC23B is responsible of the impairment in glycosylation of the membrane proteins involved in the activation of the BMP/SMADs pathway with subsequent hepcidin suppression. Most of these data were confirmed in another hepatic cell line, HepG2, stably silenced for SEC23B. Our findings suggested that the pathogenic mechanism of iron overload in CDA II is associated to both ineffective erythropoiesis and to a specific involvement of SEC23B pathogenic variants at hepatic level. Finally, we demonstrated the ability of SEC23B paralog, i.e., SEC23A, to rescue the hepcidin suppression, highlighting the functional overlap between the two SEC23 paralogs in human hepatic cells.

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Section: Discussionsupporting

confidence: 92%

SEC23B Loss-of-Function Suppresses Hepcidin Expression by Impairing Glycosylation Pathway in Human Hepatic Cells

Rosato

Marra

D’Onofrio

et al. 2022

IJMS

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“…A dose-response relationship between the level of increased SEC23A expression in SEC23B deleted HUDEP-2 cells and the degree of rescue of the erythroid differentiation defect was noted. Increased expression of SEC23A by as little as 30 and 5% in undifferentiated and differentiated HUDEP-2 cells, respectively, resulted in significant improvement of the erythroid defects resulting from SEC23B deficiency [51 ▪ ]. Taken together, these findings indicate that strategies aimed at increasing SEC23A level, even by moderate amounts, are expected to be of therapeutic value for CDA II.…”

Section: Congenital Dyserythropoietic Anemia Type IImentioning

confidence: 71%

“…To address the discrepant mouse and human phenotypes resulting from SEC23B deficiency, a large body of work was performed demonstrating that SEC23B functionally overlaps with its closely related paralogous protein SEC23A. The functional overlap between SEC23A and SEC23B was supported by several lines of evidence, including studies showing overlapping interactomes for SEC23A and SEC23B [56], complementation of the yeast sec23 by both murine and human SEC23 paralogs [56], and rescue of the perinatal mortality and pancreatic degeneration resulting from murine SEC23B deficiency by expressing Sec23a from the endogenous locus of Sec23b [51 ▪ ,56]. Examination of the expression levels of SEC23A and SEC23B in wildtype mouse and human bone marrow and pancreas tissues demonstrated a greater dependency for SEC23B in human bone marrow and mouse pancreas tissues [56–58], consistent with the SEC23B deficient phenotypes in these species.…”

Section: Congenital Dyserythropoietic Anemia Type IImentioning

confidence: 99%

“…For many years, one of the chief obstacles to studying the pathogenesis of CDA II has been the lack of a cell or animal model that recapitulate features of CDA II. However, recent generation of human erythroid cell lines (such as HUDEP-2) that can be differentiated efficiently into more mature erythroid cells resulted in the successful generation of a cellular model for CDA II [51 ▪ ]. SEC23B-deficient HUDEP-2 cells exhibited no survival or expansion defect when maintained in the pro-erythroblasts phase; however, upon differentiation into mature erythroid cells, SEC23B deleted HUDEP-2 cells exhibited reduced survival and expansion, a differentiation defect, and increased bi-nucleated cells, characteristic features of CDA II [51 ▪ ].…”

Section: Congenital Dyserythropoietic Anemia Type IImentioning

confidence: 99%

“…However, recent generation of human erythroid cell lines (such as HUDEP-2) that can be differentiated efficiently into more mature erythroid cells resulted in the successful generation of a cellular model for CDA II [51 ▪ ]. SEC23B-deficient HUDEP-2 cells exhibited no survival or expansion defect when maintained in the pro-erythroblasts phase; however, upon differentiation into mature erythroid cells, SEC23B deleted HUDEP-2 cells exhibited reduced survival and expansion, a differentiation defect, and increased bi-nucleated cells, characteristic features of CDA II [51 ▪ ]. The CDA II cell line model is expected to result in improved understanding of the pathophysiology of CDA II and to test the effectiveness of future therapies developed for the disease.…”

Section: Congenital Dyserythropoietic Anemia Type IImentioning

confidence: 99%

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The congenital dyserythropoieitic anemias: genetics and pathophysiology

King

Gallagher

Khoriaty

2021

Current Opinion in Hematology

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Purpose of reviewThe congenital dyserythropoietic anemias (CDA) are hereditary disorders characterized by ineffective erythropoiesis. This review evaluates newly developed CDA disease models, the latest advances in understanding the pathogenesis of the CDAs, and recently identified CDA genes.Recent findingsMice exhibiting features of CDAI were recently generated, demonstrating that Codanin-1 (encoded by Cdan1) is essential for primitive erythropoiesis. Additionally, Codanin-1 was found to physically interact with CDIN1, suggesting that mutations in CDAN1 and CDIN1 result in CDAI via a common mechanism. Recent advances in CDAII (which results from SEC23B mutations) have also been made. SEC23B was found to functionally overlap with its paralogous protein, SEC23A, likely explaining the absence of CDAII in SEC23B-deficient mice. In contrast, mice with erythroid-specific deletion of 3 or 4 of the Sec23 alleles exhibited features of CDAII. Increased SEC23A expression rescued the CDAII erythroid defect, suggesting a novel therapeutic strategy for the disease. Additional recent advances included the identification of new CDA genes, RACGAP1 and VPS4A, in CDAIII and a syndromic CDA type, respectively.SummaryEstablishing cellular and animal models of CDA is expected to result in improved understanding of the pathogenesis of these disorders, which may ultimately lead to the development of new therapies.

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Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo

Tang,

Xiang,

Chen

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Proteins carrying a signal peptide and/or a transmembrane domain enter the intracellular secretory pathway at the endoplasmic reticulum (ER) and are transported to the Golgi apparatus via COPII vesicles or tubules. SAR1 initiates COPII coat assembly by recruiting other coat proteins to the ER membrane. Mammalian genomes encode two SAR1 paralogs, SAR1A and SAR1B . While these paralogs exhibit ~90% amino acid sequence identity, it is unknown whether they perform distinct or overlapping functions in vivo. We now report that genetic inactivation of Sar1a in mice results in lethality during midembryogenesis. We also confirm previous reports that complete deficiency of murine Sar1b results in perinatal lethality. In contrast, we demonstrate that deletion of Sar1b restricted to hepatocytes is compatible with survival, though resulting in hypocholesterolemia that can be rescued by adenovirus-mediated overexpression of either SAR1A or SAR1B. To further examine the in vivo function of these two paralogs, we genetically engineered mice with the Sar1a coding sequence replacing that of Sar1b at the endogenous Sar1b locus. Mice homozygous for this allele survive to adulthood and are phenotypically normal, demonstrating complete or near-complete overlap in function between the two SAR1 protein paralogs in mice. These data also suggest upregulation of SAR1A gene expression as a potential approach for the treatment of SAR1B deficiency (chylomicron retention disease) in humans.

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SEC23A rescues SEC23B-deficient congenital dyserythropoietic anemia type II

Abstract: The COPII component SEC23A overlaps functionally with its paralogous protein and rescues the SEC23B-deficient CDAII defect.

Cited by 8 publications

References 84 publications

SEC23B Loss-of-Function Suppresses Hepcidin Expression by Impairing Glycosylation Pathway in Human Hepatic Cells

SEC23B Loss-of-Function Suppresses Hepcidin Expression by Impairing Glycosylation Pathway in Human Hepatic Cells

The congenital dyserythropoieitic anemias: genetics and pathophysiology

Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo

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