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Background  Congenital dyserythropoietic anemia type II (CDAII), the most common form of CDA, is an autosomal recessive condition. CDAII diagnosis is based on invasive, expensive, and time consuming tests that are available only in specialized laboratories. The recent identification of  SEC23B  mutations as the cause of CDAII opens new possibilities for the molecular diagnosis of the disease. The aim of this study was to characterize molecular genomic  SEC23B  defects in 16 unrelated patients affected by CDAII and correlate the identified genetic alterations with  SEC23B  transcript and protein levels in erythroid precursors.    Methods   SEC23B  was sequenced in 16 patients, their relatives and 100 control participants.  SEC23B  transcript level were studied by quantitative PCR (qPCR) in peripheral erythroid precursors and lymphocytes from the patients and healthy control participants. Sec23B protein content was analyzed by immunoblotting in samples of erythroblast cells from CDAII patients and healthy controls.    Results  All of the investigated cases carried  SEC23B  mutations on both alleles, with the exception of two patients in which a single heterozygous mutation was found. We identified 15 different  SEC23B  mutations, of which four represent novel mutations: p.Gln214Stop, p.Thr485Ala, p.Val637Gly, and p.Ser727Phe. The CDAII patients exhibited a 40-60% decrease of  SEC23B  mRNA levels in erythroid precursors when compared with the corresponding cell type from healthy participants. The largest decrease was observed in compound heterozygote patients with missense/nonsense mutations. In three patients, Sec23B protein levels were evaluated in erythroid precursors and found to be strictly correlated with the reduction observed at the transcript level. We also demonstrate that Sec23B mRNA expression levels in lymphocytes and erythroblasts are similar.    Conclusions  In this study, we identified four novel  SEC23B  mutations associated with CDAII disease. We also demonstrate that the genetic alteration results in a significant decrease of  SEC23B  transcript in erythroid precursors. Similar down-regulation was observed in peripheral lymphocytes, suggesting that the use of these cells might be sufficient in the identification of Sec23B gene alterations. Finally, we demonstrate that decreased Sec23B protein levels in erythroid precursors correlate with down-regulation of the  SEC23B  mRNA transcript.

Congenital Dyserythropoietic Anemia Type II: molecular analysis and expression of the SEC23B Gene