The role of genetic testing in accurate diagnosis of X-linked sideroblastic anemia: novel ALAS2 mutations and the impact of X-chromosome inactivation
This work was supported by ARETHA grant PID2021122436OB-I00 funded by MCIN/AEI/https://doi.org/10.13039/501100011033 to M.S, by grant PLEC2021-007727/AEI /https://doi.org/10.13039/501100011033/Union Europea NextGenerationEU/PRTR from MCIN to M.S. and by Deutsche Josep Carreras Leukämie-Stiftung gran...
| Autores: | , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:20.500.12328/5055 |
| Acceso en línea: | http://hdl.handle.net/20.500.12328/5055 https://dx.doi.org/10.1038/s41598-025-95590-x |
| Access Level: | acceso abierto |
| Palabra clave: | ALAS2 Anèmia sideroblàstica lligada al cromosoma X Anèmia sideroblàstica congènita Anèmia hereditària Sideroblasts en anell Mutació stop-loss Anemia sideroblástica ligada al cromosoma X Anemia sideroblástica congénita Anemia hereditaria Sideroblastos en anillo Mutación stop-loss X-linked sideroblastic anemia Congenital sideroblastic anemia Hereditary anemia Ring sideroblasts Stop-loss mutation 61 |
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The role of genetic testing in accurate diagnosis of X-linked sideroblastic anemia: novel ALAS2 mutations and the impact of X-chromosome inactivation |
| title |
The role of genetic testing in accurate diagnosis of X-linked sideroblastic anemia: novel ALAS2 mutations and the impact of X-chromosome inactivation |
| spellingShingle |
The role of genetic testing in accurate diagnosis of X-linked sideroblastic anemia: novel ALAS2 mutations and the impact of X-chromosome inactivation Jové Solavera, Daniel ALAS2 Anèmia sideroblàstica lligada al cromosoma X Anèmia sideroblàstica congènita Anèmia hereditària Sideroblasts en anell Mutació stop-loss ALAS2 Anemia sideroblástica ligada al cromosoma X Anemia sideroblástica congénita Anemia hereditaria Sideroblastos en anillo Mutación stop-loss ALAS2 X-linked sideroblastic anemia Congenital sideroblastic anemia Hereditary anemia Ring sideroblasts Stop-loss mutation 61 |
| title_short |
The role of genetic testing in accurate diagnosis of X-linked sideroblastic anemia: novel ALAS2 mutations and the impact of X-chromosome inactivation |
| title_full |
The role of genetic testing in accurate diagnosis of X-linked sideroblastic anemia: novel ALAS2 mutations and the impact of X-chromosome inactivation |
| title_fullStr |
The role of genetic testing in accurate diagnosis of X-linked sideroblastic anemia: novel ALAS2 mutations and the impact of X-chromosome inactivation |
| title_full_unstemmed |
The role of genetic testing in accurate diagnosis of X-linked sideroblastic anemia: novel ALAS2 mutations and the impact of X-chromosome inactivation |
| title_sort |
The role of genetic testing in accurate diagnosis of X-linked sideroblastic anemia: novel ALAS2 mutations and the impact of X-chromosome inactivation |
| dc.creator.none.fl_str_mv |
Jové Solavera, Daniel Rámila, Marta Ferrer, Xènia Olivella, Mireia Venturi, Veronica Morado, Marta Hernández-Rodríguez, Ines Khan, Aneal Pérez-Montero, Santiago Tornador, Cristian Germing, Ulrich Gattermann, Norbert Sanchez-Fernandez, Mayka |
| author |
Jové Solavera, Daniel |
| author_facet |
Jové Solavera, Daniel Rámila, Marta Ferrer, Xènia Olivella, Mireia Venturi, Veronica Morado, Marta Hernández-Rodríguez, Ines Khan, Aneal Pérez-Montero, Santiago Tornador, Cristian Germing, Ulrich Gattermann, Norbert Sanchez-Fernandez, Mayka |
| author_role |
author |
| author2 |
Rámila, Marta Ferrer, Xènia Olivella, Mireia Venturi, Veronica Morado, Marta Hernández-Rodríguez, Ines Khan, Aneal Pérez-Montero, Santiago Tornador, Cristian Germing, Ulrich Gattermann, Norbert Sanchez-Fernandez, Mayka |
| author2_role |
author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
ALAS2 Anèmia sideroblàstica lligada al cromosoma X Anèmia sideroblàstica congènita Anèmia hereditària Sideroblasts en anell Mutació stop-loss ALAS2 Anemia sideroblástica ligada al cromosoma X Anemia sideroblástica congénita Anemia hereditaria Sideroblastos en anillo Mutación stop-loss ALAS2 X-linked sideroblastic anemia Congenital sideroblastic anemia Hereditary anemia Ring sideroblasts Stop-loss mutation 61 |
| topic |
ALAS2 Anèmia sideroblàstica lligada al cromosoma X Anèmia sideroblàstica congènita Anèmia hereditària Sideroblasts en anell Mutació stop-loss ALAS2 Anemia sideroblástica ligada al cromosoma X Anemia sideroblástica congénita Anemia hereditaria Sideroblastos en anillo Mutación stop-loss ALAS2 X-linked sideroblastic anemia Congenital sideroblastic anemia Hereditary anemia Ring sideroblasts Stop-loss mutation 61 |
| description |
This work was supported by ARETHA grant PID2021122436OB-I00 funded by MCIN/AEI/https://doi.org/10.13039/501100011033 to M.S, by grant PLEC2021-007727/AEI /https://doi.org/10.13039/501100011033/Union Europea NextGenerationEU/PRTR from MCIN to M.S. and by Deutsche Josep Carreras Leukämie-Stiftung grant DJCLS R 14/04 to N.G. and M.S. D.J-S. hold a UIC predoctoral fellowship. X.F.-C. was partially supported by funds provided by the grant PID2021122436OB-I00 funded by MCIN/AEI/https://doi.org/10.13039/501100011033. V.V. was supported by funds provided by APU and ADISCON patient associations, UIC postdoctoral scholarship and by funds provided by RETOS COLABORACION grant RTC2019-007074-1 from MCIN/AEI/https://doi.org/10.13039/501100011033 from Spanish Ministry of Science and Innovation (MICINN). |
| publishDate |
2025 |
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2025 |
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info:eu-repo/semantics/article |
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article |
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http://hdl.handle.net/20.500.12328/5055 https://dx.doi.org/10.1038/s41598-025-95590-x |
| url |
http://hdl.handle.net/20.500.12328/5055 https://dx.doi.org/10.1038/s41598-025-95590-x |
| dc.language.none.fl_str_mv |
Inglés |
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Inglés |
| dc.relation.none.fl_str_mv |
Scientific Reports 15 |
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http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
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14 |
| dc.publisher.none.fl_str_mv |
Springer Nature |
| publisher.none.fl_str_mv |
Springer Nature |
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reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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1869409658219790336 |
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The role of genetic testing in accurate diagnosis of X-linked sideroblastic anemia: novel ALAS2 mutations and the impact of X-chromosome inactivationJové Solavera, DanielRámila, MartaFerrer, XèniaOlivella, MireiaVenturi, VeronicaMorado, MartaHernández-Rodríguez, InesKhan, AnealPérez-Montero, SantiagoTornador, CristianGerming, UlrichGattermann, NorbertSanchez-Fernandez, MaykaALAS2Anèmia sideroblàstica lligada al cromosoma XAnèmia sideroblàstica congènitaAnèmia hereditàriaSideroblasts en anellMutació stop-lossALAS2Anemia sideroblástica ligada al cromosoma XAnemia sideroblástica congénitaAnemia hereditariaSideroblastos en anilloMutación stop-lossALAS2X-linked sideroblastic anemiaCongenital sideroblastic anemiaHereditary anemiaRing sideroblastsStop-loss mutation61This work was supported by ARETHA grant PID2021122436OB-I00 funded by MCIN/AEI/https://doi.org/10.13039/501100011033 to M.S, by grant PLEC2021-007727/AEI /https://doi.org/10.13039/501100011033/Union Europea NextGenerationEU/PRTR from MCIN to M.S. and by Deutsche Josep Carreras Leukämie-Stiftung grant DJCLS R 14/04 to N.G. and M.S. D.J-S. hold a UIC predoctoral fellowship. X.F.-C. was partially supported by funds provided by the grant PID2021122436OB-I00 funded by MCIN/AEI/https://doi.org/10.13039/501100011033. V.V. was supported by funds provided by APU and ADISCON patient associations, UIC postdoctoral scholarship and by funds provided by RETOS COLABORACION grant RTC2019-007074-1 from MCIN/AEI/https://doi.org/10.13039/501100011033 from Spanish Ministry of Science and Innovation (MICINN).X-linked sideroblastic anemia (XLSA) is a hereditary disorder affecting heme biosynthesis, caused by mutations in the ALAS2 gene, which encodes the erythroid-specific enzyme 5-aminolevulinate synthase. This enzyme, which requires pyridoxal 5’-phosphate (PLP) as a cofactor, catalyzes the first and rate-limiting step of heme synthesis in erythroid cells. XLSA is characterized by hypochromic microcytic anemia and ring sideroblasts in bone marrow, with most patients showing variable degrees of response to pyridoxine supplementation; however, female carriers of ALAS2 mutations often present a distinct clinical phenotype. A comprehensive review of the literature reveals over 100 distinct ALAS2 mutations linked to XLSA in more than 240 families. Here, we report seven new patients (four female cases) initially diagnosed with various conditions, later confirmed to have X-linked Sideroblastic Anemia due to ALAS2 mutations through genetic analysis. Among these, five represent novel ALAS2 mutations, including the first ever reported stop-loss mutation in ALAS2 associated with XLSA rather than X-linked dominant protoporphyria (XLDPP). Computational modelling of six reported cases revealed that four mutations significantly impact protein structure, conformation and cofactor interaction, consistent with our enzymatic assays demonstrating reduced ALAS2 activity. Furthermore, X-chromosome studies in female probands revealed a pronounced skewing of X-chromosome, which may provide an explanation for their distinct clinical manifestations in females.info:eu-repo/semantics/publishedVersionSpringer Nature2025info:eu-repo/semantics/article14http://hdl.handle.net/20.500.12328/5055https://dx.doi.org/10.1038/s41598-025-95590-xreponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésScientific Reports15This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:20.500.12328/50552026-05-29T05:05:01Z |
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15.812429 |