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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/151683
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/151683
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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 Técnicas2025-10-22T11:55:02Zoai: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:34982025-10-22 11:55:02.605CONICET 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
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv 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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score 12.982451

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