Mutational spectrum in congenital dyserythropoietic anemia type II: Identification of 19 novel variants in <i>SEC23B</i> gene

Russo, Roberta; Esposito, Maria Rosaria; Asci, Roberta; Gambale, Antonella; Perrotta, Silverio; Ramenghi, Ugo; Forni, Gian Luca; Uygun, Vedat; Delaunay, Jean; Iolascon, Achille

doi:10.1002/ajh.21866

Cited by 40 publications

(48 citation statements)

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“…The identification of a human CDAII mutation (H757P) within this deleted C-terminal segment of SEC23B is also consistent with the importance of this domain for SEC23B function (34). Although the fusion protein does retain some interaction with SEC24A (Fig.…”

Section: Discussionsupporting

confidence: 77%

“…The more severe clinical phenotype reported in patients with compound heterozygosity for a missense and nonsense mutation compared with those with two missense alleles (34,35) is also consistent with this hypothesis.…”

Section: Discussionsupporting

confidence: 77%

“…Given the early death of Sec23b gt/gt mice, we cannot exclude the possibility that significant anemia might have become evident after birth or was being masked by dehydration in the neonate. In addition, all patients with CDAII reported to date carry at least one missense allele (20,21,34,35), suggesting that complete SEC23B deficiency might also be lethal in humans.…”

Section: Discussionmentioning

confidence: 99%

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SEC23B is required for the maintenance of murine professional secretory tissues

Tao

Zhu

Wang

et al. 2012

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

106

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In eukaryotic cells, newly synthesized secretory proteins require COPII (coat protein complex II) to exit the endoplasmic reticulum (ER). COPII contains five core components: SAR1, SEC23, SEC24, SEC13, and SEC31. SEC23 is a GTPase-activating protein that activates the SAR1 GTPase and also plays a role in cargo recognition. Missense mutations in the human COPII paralogues SEC23A and SEC23B result in craniolenticulosutural dysplasia and congenital dyserythropoietic anemia type II, respectively. We now report that mice completely deficient for SEC23B are born with no apparent anemia phenotype, but die shortly after birth, with degeneration of professional secretory tissues. In SEC23B-deficient embryonic pancreas, defects occur in exocrine and endocrine tissues shortly after differentiation. Pancreatic acini are completely devoid of zymogen granules, and the ER is severely distended. Similar ultrastructural alterations are also observed in salivary glands, but not in liver. Accumulation of proteins in the ER lumen activates the proapoptotic pathway of the unfolded protein response, suggesting a central role for apoptosis in the degeneration of these tissues in SEC23B-deficient embryos. Although maintenance of the secretory pathway should be required by all cells, our findings reveal a surprising tissue-specific dependence on SEC23B for the ER exit of highly abundant cargo, with high levels of SEC23B expression observed in professional secretory tissues. The disparate phenotypes in mouse and human could result from residual SEC23B function associated with the hypomorphic mutations observed in humans, or alternatively, might be explained by a species-specific shift in function between the closely related SEC23 paralogues. mammalian embryo abnormalities | vesicular transport protein | genetics | secretory granules | pancreatitis I n eukaryotic cells, secreted proteins and proteins that are targeted to the plasma membrane and internal organelles are synthesized in the endoplasmic reticulum (ER) and sorted through the secretory pathway. This process has been extensively studied, particularly in budding yeast (1). Proteins destined to traffic from the ER to the Golgi are packaged into COPII (coat protein complex II)-coated vesicles (2-4). COPII is composed of at least five proteins, a small GTPase SAR1 and two cytosolic protein complexes, SEC23-SEC24 and SEC13-SEC31 (5). The GTP-bound form of SAR1 binds to the ER membrane and recruits the SEC23-SEC24 heterodimer to form the "prebudding complex," which in turn recruits the outer coat composed of SEC13-SEC31 heterotetramers to complete the COPII coat structure (6).The COPII complex captures cargo into vesicles and mediates vesicle budding from the ER. Cargo recognition appears to be mediated primarily by the SEC24 subunit, which recognizes divergent export signals located in the cytosolic domain of cargo proteins (7,8). SEC23 and SAR1 also play a role in the recognition of at least a subset of cargos (9, 10). SEC23 is a GTPaseactivating protein (GAP) that activates the SAR1...

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Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

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SEC23B is required for the maintenance of murine professional secretory tissues

Tao

Zhu

Wang

et al. 2012

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

106

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“…the mutations on one or both alleles) of decreased spectrin mRNA accumulation in these cases is not known, even after mutation screening of the promoter and coding exons of the ␣-spectrin gene. Similarly, in congenital dyserythropoietic anemia type II, a recessively inherited disorder due to mutations in the SEC23B gene, a number of patients exhibit all of the phenotypic characteristics of congenital dyserythropoietic anemia type II, but a SEC23B mutation has only been identified on one allele (40,94). Both of these genes have candidate enhancers in the genomic vicinity, making these regions excellent candidates for disease-associated mutations in these patients.…”

Section: Discussionmentioning

confidence: 99%

Identification of Biologically Relevant Enhancers in Human Erythroid Cells

Steiner

Bogardus

et al. 2013

Journal of Biological Chemistry

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Background: Programs of cellular development and differentiation are controlled by enhancers. Results: Human erythroid cell type-specific enhancers are marked by p300 and groups of transcription factors. Conclusion: Enhancers are important regulators of species-specific erythroid cell structure and function. Significance: Deciphering how nonpromoter regulatory elements control gene expression in erythroid cells is important for understanding inherited and acquired hematologic disease.

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“…74 Until now, 53 different causative mutations have been described in the SEC23B gene ( Figure 3; see Online Supplementary Table S1 for complete mutational spectrum of CDAN2). 8,14,[75][76][77] Very recently, Sec23b deficient mice (Sec23b gt/gt) from ES cells with a genetrap cassette inserted into the last intron of Sec23b were generated. Sec23b gt/gt mice are born with no apparent anemia phenotype, but die shortly after birth, with degeneration of professional secretory tissues, pancreas, as well as salivary glands.…”

Section: Cda Type IImentioning

confidence: 99%

Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach

2012

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Congenital dyserythropoietic anemias belong to a group of inherited conditions characterized by a maturation arrest during erythropoiesis with a reduced reticulocyte production in contrast with erythroid hyperplasia in bone marrow. The latter shows specific morphological abnormalities that allowed for a morphological classification of these conditions mainly represented by congenital dyserythropoietic anemias types I and II. The identification of their causative genes provided evidence that these conditions have different molecular mechanisms that induce abnormal cell maturation and division. Some altered proteins seem to be involved in the chromatin assembly, such as codanin-1 in congenital dyserythropoietic anemia I. The gene involved in congenital dyserythropoietic anemia II, the most frequent form, is SEC23B. This condition seems to belong to a group of diseases attributable to defects in the transport of newly synthesized proteins from endoplasmic reticulum to the Golgi. This review will analyze recent insights in congenital dyserythropoietic anemias types I and II. It will also attempt to clarify the relationship between mutations in causative genes and the clinical phenotype of these conditions. Key words: dyserythropoiesis, congenital dyserythropoietic anemia, red blood cells, inherited anemias.Citation: Iolascon A, Esposito MR, and Russo R. Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach. Haematologica 2012;97(12): 1786-1794. doi:10.3324/haematol.2012 This is an open-access paper. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nto distinguish without molecular evaluation. 7,8 Recent identification of several causative genes could help reclassify these disorders (Table 1). Variant forms are very rare and this, up to now, has compromised further molecular studies. Linkage studies had previously been the main tool to clarify the genetics of Mendelian disorders; however, extremely rare disorders or sporadic cases caused by de novo variants are not appropriate for this type of study design. Exome sequencing is now becoming technically feasible and more cost-effective due to the recent advances in high-throughput sequence capture methods and next-generation sequencing technologies that have offered new opportunities for research into Mendelian disorders. 9 We suggest that the use of these new technologies will lead to the identification of new causative genes in CDA variants in the near future. In particular, this review will deal with new insights on the two most frequent forms of CDAs: types I and II. Epidemiology of CDAsUntil December 2011, 712 cases from 614 families were included in the German CDA Registry, 10,11 whereas 206Clinical aspects and pathogenesis of CDAs haematologica | 2012; 97 (12) 1787 © F e r r a t a S t o r t i F o u n d a t i o ncases from 183 families were enrolled in the Italian CDA registry (A Iolascon, unpublished data, 2011 Although CDA II patients are to be found right across the Italian peninsula, the maj...

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Mutational spectrum in congenital dyserythropoietic anemia type II: Identification of 19 novel variants in SEC23B gene

Cited by 40 publications

References 17 publications

SEC23B is required for the maintenance of murine professional secretory tissues

SEC23B is required for the maintenance of murine professional secretory tissues

Identification of Biologically Relevant Enhancers in Human Erythroid Cells

Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach

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