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Hypomorphic mutations of SEC23B gene account for mild phenotypes of congenital dyserythropoietic anemia type II.

ABSTRACT: Congenital dyserythropoietic anemia type II, a recessive disorder of erythroid differentiation, is due to mutations in SEC23B, a component of the core trafficking machinery COPII. In no case homozygosity or compound heterozygosity for nonsense mutation(s) was found. This study represents the first description of molecular mechanisms underlying SEC23B hypomorphic genotypes by the analysis of five novel mutations. Our findings suggest that reduction of SEC23B gene expression is not associated with CDA II severe clinical presentation; conversely, the combination of a hypomorphic allele with one functionally altered results in more severe phenotypes. We propose a mechanism of compensation SEC23A-mediated which justifies these observations.

SUBMITTER: Russo R

PROVIDER: S-EPMC3651933 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Hypomorphic mutations of SEC23B gene account for mild phenotypes of congenital dyserythropoietic anemia type II.

Russo Roberta R Langella Concetta C Esposito Maria Rosaria MR Gambale Antonella A Vitiello Francesco F Vallefuoco Fara F Ek Torben T Yang Elizabeth E Iolascon Achille A

Blood cells, molecules & diseases 20130301 1

Congenital dyserythropoietic anemia type II, a recessive disorder of erythroid differentiation, is due to mutations in SEC23B, a component of the core trafficking machinery COPII. In no case homozygosity or compound heterozygosity for nonsense mutation(s) was found. This study represents the first description of molecular mechanisms underlying SEC23B hypomorphic genotypes by the analysis of five novel mutations. Our findings suggest that reduction of SEC23B gene expression is not associated with ...[more]

PMID: 23453696

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Project description:BackgroundCongenital 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.MethodsSEC23B 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.ResultsAll 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.ConclusionsIn 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.

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Hypomorphic mutations of SEC23B gene account for mild phenotypes of congenital dyserythropoietic anemia type II.

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Hypomorphic mutations of SEC23B gene account for mild phenotypes of congenital dyserythropoietic anemia type II.

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