New Cases and Mutations in SEC23B Gene Causing Congenital Dyserythropoietic Anemia Type II
| Autor: | Musri, Melina Mara, Venturi, Veronica, Ferrer, Xènia, Romero Cortadellas, Lídia, Hernandez Viedma, Gonzalo, Leoz Allegretti, María del Pilar, Beneitez Pastor, David, Ortuño Cabrero, Ana |
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| Přispěvatelé: | Institut Català de la Salut, [Musri MM] BloodGenetics S.L. Diagnostics in Inherited Blood Diseases, Esplugues de Llobregat, Spain. [Venturi V, Romero-Cortadellas L] Department of Basic Sciences, Iron Metabolism: Regulation and Diseases Group, Universitat Internacional de Catalunya, Sant Cugat del Vallès, Spain. [Ferrer-Cortès X, Hernández G] BloodGenetics S.L. Diagnostics in Inherited Blood Diseases, Esplugues de Llobregat, Spain. Department of Basic Sciences, Iron Metabolism: Regulation and Diseases Group, Universitat Internacional de Catalunya, Sant Cugat del Vallès, Spain. [Leoz P] Red Blood Cell Disorders Unit, Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. [Beneitez Pastor D, Ortuño Cabrero A] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: |
Anomalies cromosòmiques
Hemic and Lymphatic Diseases::Hematologic Diseases::Anemia::Anemia Hemolytic::Anemia Hemolytic Congenital::Anemia Dyserythropoietic Congenital [DISEASES] Sang - Malalties - Aspectes genètics Otros calificadores::Otros calificadores::/genética [Otros calificadores] Other subheadings::Other subheadings::/genetics [Other subheadings] Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES] enfermedades hematológicas y linfáticas::enfermedades hematológicas::anemia::anemia hemolítica::anemia hemolítica congénita::anemia diseritropoyética congénita [ENFERMEDADES] Anèmia - Aspectes genètics Eritròcits fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS] |
| Zdroj: | Scientia |
| Popis: | Hereditary anemias; Ineffective erythropoiesis; Rare blood disease Anèmies hereditàries; Eritropoesi ineficaç; Malaltia rara de la sang Anemias hereditarias; Eritropoyesis ineficaz; Enfermedad rara de la sangre 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. This work was supported by NEOTEC grant SNEO-20191246 from Spanish CDTI to C.T., RETOS COLABORACION grant RTC2019-007074-1 from: MCIN/AEI/10.13039/501100011033 from Spanish Ministry of Science and Innovation (MICINN) to C.T. and M.S.; ARETHA grant PID2021-122436OB-I00 funded by MCIN/AEI/10.13039/501100011033 to M.S.; RTI-2018-101735-B-I100 from MCIN/AEI/10.13039/501100011033/ERDF “A way to make Europe” from the Spanish Ministry of Science and Innovation (MICINN) to M.S. M.M.M. is supported by a Marie Curie Fellowship from the European Commission under Horizon 2020 Framework Program Project: 894737. G.H. is supported by funds provided by the APU and ADISCON patient associations. L.R.-C. holds an FI-AGAUR predoctoral fellowship (2020FI-B00038) from Generalitat de Catalunya. X.F.-C. is partially supported by funds provided by the grant RTI-2018-101735-B-I100 from MCIN/AEI/10.13039/501100011033/ERDF “A way to make Europe”. V.V. was supported by funds provided by APU and ADISCON patient associations and UIC postdoctoral scholarship; she is currently supported by funds provided by RETOS COLABORACION grant RTC2019-007074-1 from MCIN/AEI/10.13039/501100011033 from Spanish Ministry of Science and Innovation (MICINN). |
| Databáze: | OpenAIRE |
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