New Cases and Mutations in SEC23B Gene Causing Congenital Dyserythropoietic Anemia Type II.

Fecha de publicación: 09/06/2023 Fecha Ahead of Print: 09/06/2023

Autores de IIS La Fe

María Leonor Senent Peris

Autor

Participantes ajenos a IIS La Fe

Musri, Melina Mara
Venturi, Veronica
Ferrer-Cortes, Xenia
Romero-Cortadellas, Lidia
Hernandez, Gonzalo
Leoz, Pilar
Ricard Andres, Maria Pilar
Morado, Marta
Fernández Valle MDC
Beneitez Pastor, David
Ortuño Cabrero A
Moreno Gamiz, Maite
Perez-Valencia, Amanda Isabel
Perez-Montero, Santiago
Tornador, Cristian
Sanchez, Mayka

Grupos

Hematología y Hemoterapia

Investigador Principal

Javier De La Rubia Comos

Abstract

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 SEC23B 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 SEC23B 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 SEC23B variants, describe nine new CDA II cases accounting for six previously unreported variants, and discuss innovative therapeutic approaches for CDA II.

Datos de la publicación

ISSN/ISSNe:: 1661-6596, 1661-6596
Tipo:: Article
Páginas:: -
DOI:: 10.3390/ijms24129935
Factor de Impacto:: 1,176 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Musri, Melina Mara:: BloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, Spain
Venturi, Veronica:: Department of Basic Sciences, Iron Metabolism: Regulation and Diseases Group, Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, Spain
Ferrer-Cortes, Xenia:: BloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, Spain

Department of Basic Sciences, Iron Metabolism: Regulation and Diseases Group, Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, Spain
Romero-Cortadellas, Lidia:: Department of Basic Sciences, Iron Metabolism: Regulation and Diseases Group, Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, Spain
Hernandez, Gonzalo:: BloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, Spain

Department of Basic Sciences, Iron Metabolism: Regulation and Diseases Group, Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, Spain
Leoz, Pilar:: Red Blood Cell Disorders Unit, Department of Hematology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
Ricard Andres, Maria Pilar:: Hematology and Hemotherapy, Hospital Universitario Fundación Alcorcón, Avda Budapest, 28922 Alcorcon, Spain
Morado, Marta:: Department of Hematology, University Hospital La Paz, 28046 Madrid, Spain
Fernández Valle MDC:: Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain
Beneitez Pastor, David:: Red Blood Cell Disorders Unit, Hematology Department, Hospital Universitari Vall d'Hebron, VHIO, VHIR, 08035 Barcelona, Spain
Ortuño Cabrero A:: Red Blood Cell Disorders Unit, Hematology Department, Hospital Universitari Vall d'Hebron, VHIO, VHIR, 08035 Barcelona, Spain
Moreno Gamiz, Maite:: Hospital Universitario Cruces, 48903 Barakaldo, Spain
Senent Peris, Leonor:: Laboratory of Cytomorphology, Unity of Hematologic Diagnostic, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
Perez-Valencia, Amanda Isabel:: Department of Hematology, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
Perez-Montero, Santiago:: BloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, Spain
Tornador, Cristian:: BloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, Spain
Sanchez, Mayka:: BloodGenetics S.L. Diagnostics in Inherited Blood Diseases, 08950 Esplugues de Llobregat, Spain

Department of Basic Sciences, Iron Metabolism: Regulation and Diseases Group, Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, Spain