SEC23B – Congenital Dyserythropoietic Anemia Type II

Congenital Dyserythropoietic Anemia Type II (CDA II) is an autosomal recessive disorder characterized by ineffective erythropoiesis, binucleated erythroblasts and hypoglycosylation of red blood cell membrane proteins. The SEC23B gene encodes a core COPII coat protein required for ER-to-Golgi trafficking in erythroid precursors. Biallelic SEC23B variants disrupt Golgi processing, leading to impaired erythrocyte maturation and chronic anemia.

Genetic studies in 13 unrelated probands from 10 families identified 12 different SEC23B mutations (six missense, two frameshift, one splice, three nonsense) (PMID:19621418). Subsequent sequencing of 42 patients revealed 22 variants, including seven novel alleles, and genotype–phenotype correlation showed more severe anemia in compound missense–nonsense genotypes (PMID:20015893). Analysis of 101 patients uncovered 54 distinct mutations, confirming high allelic heterogeneity and minimal genotype–phenotype overlap (PMID:27471141). A representative pathogenic allele is c.1489C>T (p.Arg497Cys).

Segregation analysis across multiple consanguineous pedigrees demonstrates autosomal recessive inheritance, with at least three affected sib pairs showing concordant biallelic SEC23B variants and CDA II phenotype. A notable asymptomatic homozygote highlights variable expressivity and potential modifiers (PMID:10519996).

Functional assays reveal that SEC23B hypomorphic alleles reduce mRNA and protein levels by 40–60% in erythroid precursors, correlating with disease severity (PMID:22208203). Hypomorphic and deleterious alleles alter COPII assembly and ER stress responses, while in vitro rescue by increased SEC23A expression restores normal erythroid differentiation (PMID:23453696; PMID:34818036).

Murine models of global Sec23b deficiency exhibit perinatal pancreatic degeneration without CDA II, whereas erythroid-specific deletion of three or four Sec23 alleles yields CDA II-like dyserythropoiesis, confirming a dose-dependent requirement for SEC23B in erythropoiesis (PMID:27297878).

Collectively, over 180 probands from >90 families, robust segregation, extensive variant spectrum and concordant functional and animal data establish a Definitive gene–disease relationship. SEC23B molecular testing informs diagnosis, genetic counseling and guides curative hematopoietic stem cell transplantation decisions.

References

• Human Mutation • 2009 • Congenital dyserythropoietic anemia type II (CDAII) is caused by mutations in the SEC23B gene. PMID:19621418
• Haematologica • 2010 • Molecular analysis of 42 patients with congenital dyserythropoietic anemia type II: new mutations in the SEC23B gene and a search for a genotype-phenotype relationship. PMID:20015893
• British Journal of Haematology • 2016 • Analysis of a cohort of 101 CDAII patients: description of 24 new molecular variants and genotype-phenotype correlations. PMID:27471141
• Orphanet Journal of Rare Diseases • 2011 • Congenital dyserythropoietic anemia type II: molecular analysis and expression of the SEC23B gene. PMID:22208203
• Blood Cells, Molecules & Diseases • 2013 • Hypomorphic mutations of SEC23B gene account for mild phenotypes of congenital dyserythropoietic anemia type II. PMID:23453696
• Science Advances • 2021 • SEC23A rescues SEC23B-deficient congenital dyserythropoietic anemia type II. PMID:34818036
• Scientific Reports • 2016 • Pancreatic SEC23B deficiency is sufficient to explain the perinatal lethality of germline SEC23B deficiency in mice. PMID:27297878
• British Journal of Haematology • 1999 • Suppression of CDA II expression in a homozygote. PMID:10519996

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