New Cases and Mutations in <i>SEC23B</i> Gene Causing Congenital Dyserythropoietic Anemia Type II
Congenital dyserythropoietic anemia type II (CDA II) is an inherited autosomal recessive blood disorder which belongs to the wide group of ineffective erythropoiesis conditions. It is characterized by mild to severe normocytic anemia, jaundice, and splenomegaly owing to the hemolytic component. This...
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MDPI AG
2023-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/12/9935 |
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| author | Melina Mara Musri Veronica Venturi Xènia Ferrer-Cortès Lídia Romero-Cortadellas Gonzalo Hernández Pilar Leoz María Pilar Ricard Andrés Marta Morado María del Carmen Fernández Valle David Beneitez Pastor Ana Ortuño Cabrero Maite Moreno Gamiz Leonor Senent Peris Amanda Isabel Perez-Valencia Santiago Pérez-Montero Cristian Tornador Mayka Sánchez |
| author_facet | Melina Mara Musri Veronica Venturi Xènia Ferrer-Cortès Lídia Romero-Cortadellas Gonzalo Hernández Pilar Leoz María Pilar Ricard Andrés Marta Morado María del Carmen Fernández Valle David Beneitez Pastor Ana Ortuño Cabrero Maite Moreno Gamiz Leonor Senent Peris Amanda Isabel Perez-Valencia Santiago Pérez-Montero Cristian Tornador Mayka Sánchez |
| author_sort | Melina Mara Musri |
| collection | DOAJ |
| description | Congenital dyserythropoietic anemia type II (CDA II) is an inherited autosomal recessive blood disorder which belongs to the wide group of ineffective erythropoiesis conditions. It is characterized by mild to severe normocytic anemia, jaundice, and splenomegaly owing to the hemolytic component. This often leads to liver iron overload and gallstones. CDA II is caused by biallelic mutations in the <i>SEC23B</i> gene. In this study, we report 9 new CDA II cases and identify 16 pathogenic variants, 6 of which are novel. The newly reported variants in SEC23B include three missenses (p.Thr445Arg, p.Tyr579Cys, and p.Arg701His), one frameshift (p.Asp693GlyfsTer2), and two splicing variants (c.1512-2A>G, and the complex intronic variant c.1512-3delinsTT linked to c.1512-16_1512-7delACTCTGGAAT in the same allele). Computational analyses of the missense variants indicated a loss of key residue interactions within the beta sheet and the helical and gelsolin domains, respectively. Analysis of SEC23B protein levels done in patient-derived lymphoblastoid cell lines (LCLs) showed a significant decrease in SEC23B protein expression, in the absence of SEC23A compensation. Reduced <i>SEC23B</i> mRNA expression was only detected in two probands carrying nonsense and frameshift variants; the remaining patients showed either higher gene expression levels or no expression changes at all. The skipping of exons 13 and 14 in the newly reported complex variant c.1512-3delinsTT/c.1512-16_1512-7delACTCTGGAAT results in a shorter protein isoform, as assessed by RT-PCR followed by Sanger sequencing. In this work, we summarize a comprehensive spectrum of <i>SEC23B</i> variants, describe nine new CDA II cases accounting for six previously unreported variants, and discuss innovative therapeutic approaches for CDA II. |
| first_indexed | 2024-03-11T02:23:00Z |
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| id | doaj.art-f544ba52d5e34f1fadc2230634bf24b6 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T02:23:00Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f544ba52d5e34f1fadc2230634bf24b62023-11-18T10:46:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-06-012412993510.3390/ijms24129935New Cases and Mutations in <i>SEC23B</i> Gene Causing Congenital Dyserythropoietic Anemia Type IIMelina Mara Musri0Veronica Venturi1Xènia Ferrer-Cortès2Lídia Romero-Cortadellas3Gonzalo Hernández4Pilar Leoz5María Pilar Ricard Andrés6Marta Morado7María del Carmen Fernández Valle8David Beneitez Pastor9Ana Ortuño Cabrero10Maite Moreno Gamiz11Leonor Senent Peris12Amanda Isabel Perez-Valencia13Santiago Pérez-Montero14Cristian Tornador15Mayka Sánchez16BloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, SpainDepartment of Basic Sciences, Iron Metabolism: Regulation and Diseases Group, Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, SpainBloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, SpainDepartment of Basic Sciences, Iron Metabolism: Regulation and Diseases Group, Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, SpainBloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, SpainRed Blood Cell Disorders Unit, Department of Hematology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, SpainHematology and Hemotherapy, Hospital Universitario Fundación Alcorcón, Avda Budapest, 28922 Alcorcon, SpainDepartment of Hematology, University Hospital La Paz, 28046 Madrid, SpainHospital Universitario Puerta del Mar, 11009 Cádiz, SpainRed Blood Cell Disorders Unit, Hematology Department, Hospital Universitari Vall d’Hebron, VHIO, VHIR, 08035 Barcelona, SpainRed Blood Cell Disorders Unit, Hematology Department, Hospital Universitari Vall d’Hebron, VHIO, VHIR, 08035 Barcelona, SpainHospital Universitario Cruces, 48903 Barakaldo, SpainLaboratory of Cytomorphology, Unity of Hematologic Diagnostic, Hospital Universitari i Politècnic La Fe, 46026 Valencia, SpainDepartment of Hematology, Hospital Clínic de Barcelona, 08036 Barcelona, SpainBloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, SpainBloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, SpainBloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, SpainCongenital dyserythropoietic anemia type II (CDA II) is an inherited autosomal recessive blood disorder which belongs to the wide group of ineffective erythropoiesis conditions. It is characterized by mild to severe normocytic anemia, jaundice, and splenomegaly owing to the hemolytic component. This often leads to liver iron overload and gallstones. CDA II is caused by biallelic mutations in the <i>SEC23B</i> gene. In this study, we report 9 new CDA II cases and identify 16 pathogenic variants, 6 of which are novel. The newly reported variants in SEC23B include three missenses (p.Thr445Arg, p.Tyr579Cys, and p.Arg701His), one frameshift (p.Asp693GlyfsTer2), and two splicing variants (c.1512-2A>G, and the complex intronic variant c.1512-3delinsTT linked to c.1512-16_1512-7delACTCTGGAAT in the same allele). Computational analyses of the missense variants indicated a loss of key residue interactions within the beta sheet and the helical and gelsolin domains, respectively. Analysis of SEC23B protein levels done in patient-derived lymphoblastoid cell lines (LCLs) showed a significant decrease in SEC23B protein expression, in the absence of SEC23A compensation. Reduced <i>SEC23B</i> mRNA expression was only detected in two probands carrying nonsense and frameshift variants; the remaining patients showed either higher gene expression levels or no expression changes at all. The skipping of exons 13 and 14 in the newly reported complex variant c.1512-3delinsTT/c.1512-16_1512-7delACTCTGGAAT results in a shorter protein isoform, as assessed by RT-PCR followed by Sanger sequencing. In this work, we summarize a comprehensive spectrum of <i>SEC23B</i> variants, describe nine new CDA II cases accounting for six previously unreported variants, and discuss innovative therapeutic approaches for CDA II.https://www.mdpi.com/1422-0067/24/12/9935congenital dyserythropoietic anemiaCDA type IISEC23Bhereditary anemiasineffective erythropoiesisrare blood disease |
| spellingShingle | Melina Mara Musri Veronica Venturi Xènia Ferrer-Cortès Lídia Romero-Cortadellas Gonzalo Hernández Pilar Leoz María Pilar Ricard Andrés Marta Morado María del Carmen Fernández Valle David Beneitez Pastor Ana Ortuño Cabrero Maite Moreno Gamiz Leonor Senent Peris Amanda Isabel Perez-Valencia Santiago Pérez-Montero Cristian Tornador Mayka Sánchez New Cases and Mutations in <i>SEC23B</i> Gene Causing Congenital Dyserythropoietic Anemia Type II International Journal of Molecular Sciences congenital dyserythropoietic anemia CDA type II SEC23B hereditary anemias ineffective erythropoiesis rare blood disease |
| title | New Cases and Mutations in <i>SEC23B</i> Gene Causing Congenital Dyserythropoietic Anemia Type II |
| title_full | New Cases and Mutations in <i>SEC23B</i> Gene Causing Congenital Dyserythropoietic Anemia Type II |
| title_fullStr | New Cases and Mutations in <i>SEC23B</i> Gene Causing Congenital Dyserythropoietic Anemia Type II |
| title_full_unstemmed | New Cases and Mutations in <i>SEC23B</i> Gene Causing Congenital Dyserythropoietic Anemia Type II |
| title_short | New Cases and Mutations in <i>SEC23B</i> Gene Causing Congenital Dyserythropoietic Anemia Type II |
| title_sort | new cases and mutations in i sec23b i gene causing congenital dyserythropoietic anemia type ii |
| topic | congenital dyserythropoietic anemia CDA type II SEC23B hereditary anemias ineffective erythropoiesis rare blood disease |
| url | https://www.mdpi.com/1422-0067/24/12/9935 |
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