SEC23B – Congenital Dyserythropoietic Anemia

Congenital dyserythropoietic anemias (CDAs) are inherited disorders marked by ineffective erythropoiesis, hemolysis, and characteristic erythroblast morphology. CDA type II (CDAII) is the most common form and is caused by biallelic mutations in SEC23B, a COPII coat complex component involved in ER-to-Golgi transport (PMID:20381388). Patients present with mild to severe normocytic anemia, jaundice, splenomegaly, and iron overload due to chronic hemolysis.

Autosomal recessive inheritance is established by compound heterozygous and homozygous mutations in SEC23B. An 18-year-old with lifelong anemia, jaundice, and splenomegaly carried c.40C>T (p.Arg14Trp) and c.490del (p.Val164TrpfsTer3) (PMID:29846281). Two fetuses with hydrops foetalis harbored Glu109Lys/Cys66Tyr and Glu109Lys/Arg701Cys compound variants, confirming severe intrauterine presentation (PMID:20381388). A founder missense variant c.325G>A (p.Glu109Lys) was identified in 10 of 11 Moroccan Jewish patients across 8 families, with haplotype conservation (PMID:21252497).

Segregation analyses in multiple pedigrees demonstrate co-segregation of SEC23B variants with CDAII phenotypes. Over 45 probands from more than 20 unrelated families have been reported, including both missense and loss-of-function alleles such as c.325G>A (p.Glu109Lys) and c.367C>T (p.Arg123Ter) (PMID:20941788). No cases of biallelic truncating mutations suggest essential roles for residual protein function. The variant spectrum includes missense, nonsense, splice-site, and small indel alleles without evidence of recurrent private mutations outside specific populations.

Functional studies reveal hypomorphic and compensatory mechanisms. Five novel hypomorphic alleles reduce SEC23B expression without severe phenotype, implicating partial loss of function (PMID:23453696). Hematopoietic-restricted Sec23b knockout mice lack CDAII features, while pancreatic Sec23b deficiency causes perinatal lethality, indicating tissue-specific paralog compensation (PMID:27297878). Human and murine SEC23A rescue SEC23B deficiency in vivo, restoring erythroid maturation and confirming functional interchangeability of COPII paralogs (PMID:30065114).

No studies have definitively refuted the association, though absence of biallelic null genotypes underscores the essential nature of SEC23B. Alternative phenotypes have not been reported in recessive carriers. Heterozygous variants in SEC23B predispose to cancer syndromes but remain distinct from the anemia phenotype.

In summary, biallelic SEC23B mutations cause autosomal recessive CDAII with consistent clinical features, robust segregation across diverse populations, and concordant functional data. Genetic testing for SEC23B variants enables accurate diagnosis, informs prognosis, and may guide emerging SEC23A-based therapies.

References

• Journal of pediatric hematology/oncology • 2018 • Identification of a Novel Mutation in the SEC23B Gene Associated With Congenital Dyserythropoietic Anemia Type II Through the Use of Next-generation Sequencing Panel in an Undiagnosed Case of Nonimmune Hereditary Hemolytic Anemia PMID:29846281
• Blood cells, molecules & diseases • 2010 • CDAII presenting as hydrops foetalis: molecular characterization of two cases PMID:20381388
• Acta haematologica • 2011 • E109K is a SEC23B founder mutation among Israeli Moroccan Jewish patients with congenital dyserythropoietic anemia type II PMID:21252497
• American journal of hematology • 2010 • Mutational spectrum in congenital dyserythropoietic anemia type II: identification of 19 novel variants in SEC23B gene PMID:20941788
• Blood cells, molecules & diseases • 2013 • Hypomorphic mutations of SEC23B gene account for mild phenotypes of congenital dyserythropoietic anemia type II PMID:23453696
• Proceedings of the National Academy of Sciences of the United States of America • 2018 • Functions of the COPII gene paralogs SEC23A and SEC23B are interchangeable in vivo PMID:30065114

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