Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency
- Autores
- Eskandarian, Zoya; Fliegauf, Manfred; Bulashevska, Alla; Proietti, Michele; Hague, Rosie; Smulski, Cristian Roberto; Schubert, Desirée; Warnatz, Klaus; Grimbacher, Bodo
- Año de publicación
- 2019
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency. Patients with CVID are prone to recurrent bacterial infection due to the failure of adequate immunoglobulin production. Monogenetic defects have been identified in ~25% of CVID patients. Recently, mutations in IKZF1, encoding the zinc-finger transcription factor IKAROS which is broadly expressed in hematopoietic cells, have been associated with a CVID-like phenotype. Herein we describe 11 patients with heterozygous IKZF1 variants from eight different families with autosomal dominant CVID and two siblings with an IKZF1 variant presenting with inflammatory bowel disease (IBD). This study shows that mutations affecting the DNA binding domain of IKAROS can impair the interaction with the target DNA sequence thereby preventing heterochromatin and pericentromeric localization (HC-PC) of the protein. Our results also indicate an impairment of pericentromeric localization of IKAROS by overexpression of a truncated variant, caused by an immature stop codon in IKZF1. We also describe an additional variant in TNFSF10, encoding Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), additionally presented in individuals of Family A. Our results indicate that this variant may impair the TRAIL-induced apoptosis in target cell lines and prohibit the NFκB activation by TRAIL and may act as a modifier in Family A.
Fil: Eskandarian, Zoya. Albert Ludwigs University of Freiburg; Alemania
Fil: Fliegauf, Manfred. Albert Ludwigs University of Freiburg; Alemania
Fil: Bulashevska, Alla. Albert Ludwigs University of Freiburg; Alemania
Fil: Proietti, Michele. Albert Ludwigs University of Freiburg; Alemania
Fil: Hague, Rosie. Royal Hospital For Children; Reino Unido
Fil: Smulski, Cristian Roberto. Albert Ludwigs University of Freiburg; Alemania. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina
Fil: Schubert, Desirée. Albert Ludwigs University of Freiburg; Alemania
Fil: Warnatz, Klaus. Albert Ludwigs University of Freiburg; Alemania
Fil: Grimbacher, Bodo. Albert Ludwigs University of Freiburg; Alemania. University College London; Reino Unido - Materia
-
CVID
IKAROS
MONOGENIC DEFECTS
NUCLEAR LOCALIZATION
TRAIL DNA BINDING - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/151683
Ver los metadatos del registro completo
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Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary ImmunodeficiencyEskandarian, ZoyaFliegauf, ManfredBulashevska, AllaProietti, MicheleHague, RosieSmulski, Cristian RobertoSchubert, DesiréeWarnatz, KlausGrimbacher, BodoCVIDIKAROSMONOGENIC DEFECTSNUCLEAR LOCALIZATIONTRAIL DNA BINDINGhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency. Patients with CVID are prone to recurrent bacterial infection due to the failure of adequate immunoglobulin production. Monogenetic defects have been identified in ~25% of CVID patients. Recently, mutations in IKZF1, encoding the zinc-finger transcription factor IKAROS which is broadly expressed in hematopoietic cells, have been associated with a CVID-like phenotype. Herein we describe 11 patients with heterozygous IKZF1 variants from eight different families with autosomal dominant CVID and two siblings with an IKZF1 variant presenting with inflammatory bowel disease (IBD). This study shows that mutations affecting the DNA binding domain of IKAROS can impair the interaction with the target DNA sequence thereby preventing heterochromatin and pericentromeric localization (HC-PC) of the protein. Our results also indicate an impairment of pericentromeric localization of IKAROS by overexpression of a truncated variant, caused by an immature stop codon in IKZF1. We also describe an additional variant in TNFSF10, encoding Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), additionally presented in individuals of Family A. Our results indicate that this variant may impair the TRAIL-induced apoptosis in target cell lines and prohibit the NFκB activation by TRAIL and may act as a modifier in Family A.Fil: Eskandarian, Zoya. Albert Ludwigs University of Freiburg; AlemaniaFil: Fliegauf, Manfred. Albert Ludwigs University of Freiburg; AlemaniaFil: Bulashevska, Alla. Albert Ludwigs University of Freiburg; AlemaniaFil: Proietti, Michele. Albert Ludwigs University of Freiburg; AlemaniaFil: Hague, Rosie. Royal Hospital For Children; Reino UnidoFil: Smulski, Cristian Roberto. Albert Ludwigs University of Freiburg; Alemania. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; ArgentinaFil: Schubert, Desirée. Albert Ludwigs University of Freiburg; AlemaniaFil: Warnatz, Klaus. Albert Ludwigs University of Freiburg; AlemaniaFil: Grimbacher, Bodo. Albert Ludwigs University of Freiburg; Alemania. University College London; Reino UnidoFrontiers Media2019-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/151683Eskandarian, Zoya; Fliegauf, Manfred; Bulashevska, Alla; Proietti, Michele; Hague, Rosie; et al.; Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency; Frontiers Media; Frontiers in Immunology; 10; 4-2019; 1-181664-3224CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/article/10.3389/fimmu.2019.00568/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fimmu.2019.00568info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:22:16Zoai:ri.conicet.gov.ar:11336/151683instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:22:16.563CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency |
title |
Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency |
spellingShingle |
Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency Eskandarian, Zoya CVID IKAROS MONOGENIC DEFECTS NUCLEAR LOCALIZATION TRAIL DNA BINDING |
title_short |
Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency |
title_full |
Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency |
title_fullStr |
Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency |
title_full_unstemmed |
Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency |
title_sort |
Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency |
dc.creator.none.fl_str_mv |
Eskandarian, Zoya Fliegauf, Manfred Bulashevska, Alla Proietti, Michele Hague, Rosie Smulski, Cristian Roberto Schubert, Desirée Warnatz, Klaus Grimbacher, Bodo |
author |
Eskandarian, Zoya |
author_facet |
Eskandarian, Zoya Fliegauf, Manfred Bulashevska, Alla Proietti, Michele Hague, Rosie Smulski, Cristian Roberto Schubert, Desirée Warnatz, Klaus Grimbacher, Bodo |
author_role |
author |
author2 |
Fliegauf, Manfred Bulashevska, Alla Proietti, Michele Hague, Rosie Smulski, Cristian Roberto Schubert, Desirée Warnatz, Klaus Grimbacher, Bodo |
author2_role |
author author author author author author author author |
dc.subject.none.fl_str_mv |
CVID IKAROS MONOGENIC DEFECTS NUCLEAR LOCALIZATION TRAIL DNA BINDING |
topic |
CVID IKAROS MONOGENIC DEFECTS NUCLEAR LOCALIZATION TRAIL DNA BINDING |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency. Patients with CVID are prone to recurrent bacterial infection due to the failure of adequate immunoglobulin production. Monogenetic defects have been identified in ~25% of CVID patients. Recently, mutations in IKZF1, encoding the zinc-finger transcription factor IKAROS which is broadly expressed in hematopoietic cells, have been associated with a CVID-like phenotype. Herein we describe 11 patients with heterozygous IKZF1 variants from eight different families with autosomal dominant CVID and two siblings with an IKZF1 variant presenting with inflammatory bowel disease (IBD). This study shows that mutations affecting the DNA binding domain of IKAROS can impair the interaction with the target DNA sequence thereby preventing heterochromatin and pericentromeric localization (HC-PC) of the protein. Our results also indicate an impairment of pericentromeric localization of IKAROS by overexpression of a truncated variant, caused by an immature stop codon in IKZF1. We also describe an additional variant in TNFSF10, encoding Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), additionally presented in individuals of Family A. Our results indicate that this variant may impair the TRAIL-induced apoptosis in target cell lines and prohibit the NFκB activation by TRAIL and may act as a modifier in Family A. Fil: Eskandarian, Zoya. Albert Ludwigs University of Freiburg; Alemania Fil: Fliegauf, Manfred. Albert Ludwigs University of Freiburg; Alemania Fil: Bulashevska, Alla. Albert Ludwigs University of Freiburg; Alemania Fil: Proietti, Michele. Albert Ludwigs University of Freiburg; Alemania Fil: Hague, Rosie. Royal Hospital For Children; Reino Unido Fil: Smulski, Cristian Roberto. Albert Ludwigs University of Freiburg; Alemania. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina Fil: Schubert, Desirée. Albert Ludwigs University of Freiburg; Alemania Fil: Warnatz, Klaus. Albert Ludwigs University of Freiburg; Alemania Fil: Grimbacher, Bodo. Albert Ludwigs University of Freiburg; Alemania. University College London; Reino Unido |
description |
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency. Patients with CVID are prone to recurrent bacterial infection due to the failure of adequate immunoglobulin production. Monogenetic defects have been identified in ~25% of CVID patients. Recently, mutations in IKZF1, encoding the zinc-finger transcription factor IKAROS which is broadly expressed in hematopoietic cells, have been associated with a CVID-like phenotype. Herein we describe 11 patients with heterozygous IKZF1 variants from eight different families with autosomal dominant CVID and two siblings with an IKZF1 variant presenting with inflammatory bowel disease (IBD). This study shows that mutations affecting the DNA binding domain of IKAROS can impair the interaction with the target DNA sequence thereby preventing heterochromatin and pericentromeric localization (HC-PC) of the protein. Our results also indicate an impairment of pericentromeric localization of IKAROS by overexpression of a truncated variant, caused by an immature stop codon in IKZF1. We also describe an additional variant in TNFSF10, encoding Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), additionally presented in individuals of Family A. Our results indicate that this variant may impair the TRAIL-induced apoptosis in target cell lines and prohibit the NFκB activation by TRAIL and may act as a modifier in Family A. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-04 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/151683 Eskandarian, Zoya; Fliegauf, Manfred; Bulashevska, Alla; Proietti, Michele; Hague, Rosie; et al.; Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency; Frontiers Media; Frontiers in Immunology; 10; 4-2019; 1-18 1664-3224 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/151683 |
identifier_str_mv |
Eskandarian, Zoya; Fliegauf, Manfred; Bulashevska, Alla; Proietti, Michele; Hague, Rosie; et al.; Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency; Frontiers Media; Frontiers in Immunology; 10; 4-2019; 1-18 1664-3224 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/article/10.3389/fimmu.2019.00568/full info:eu-repo/semantics/altIdentifier/doi/10.3389/fimmu.2019.00568 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Frontiers Media |
publisher.none.fl_str_mv |
Frontiers Media |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1844614213667913728 |
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13.070432 |