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A Unique Heterozygous CARD11 Mutation Combines Pathogenic Features of Both Gain- and Loss-of-Function Patients in a Four-Generation Family
CARD11 is a lymphocyte-specific scaffold molecule required for proper activation of B- and T-cells in response to antigen. Germline gain-of-function (GOF) mutations in the CARD11 gene cause a unique B cell lymphoproliferative disorder known as B cell Expansion with NF-κB and T cell Anergy (BENTA). I...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299974/ https://www.ncbi.nlm.nih.gov/pubmed/30619304 http://dx.doi.org/10.3389/fimmu.2018.02944 |
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author | Desjardins, Marylin Arjunaraja, Swadhinya Stinson, Jeffrey R. Dorjbal, Batsukh Sundaresan, Janani Niemela, Julie Raffeld, Mark Matthews, Helen F. Wang, Angela Angelus, Pamela Su, Helen C. Mazer, Bruce D. Snow, Andrew L. |
author_facet | Desjardins, Marylin Arjunaraja, Swadhinya Stinson, Jeffrey R. Dorjbal, Batsukh Sundaresan, Janani Niemela, Julie Raffeld, Mark Matthews, Helen F. Wang, Angela Angelus, Pamela Su, Helen C. Mazer, Bruce D. Snow, Andrew L. |
author_sort | Desjardins, Marylin |
collection | PubMed |
description | CARD11 is a lymphocyte-specific scaffold molecule required for proper activation of B- and T-cells in response to antigen. Germline gain-of-function (GOF) mutations in the CARD11 gene cause a unique B cell lymphoproliferative disorder known as B cell Expansion with NF-κB and T cell Anergy (BENTA). In contrast, patients carrying loss-of-function (LOF), dominant negative (DN) CARD11 mutations present with severe atopic disease. Interestingly, both GOF and DN CARD11 variants cause primary immunodeficiency, with recurrent bacterial and viral infections, likely resulting from impaired adaptive immune responses. This report describes a unique four-generation family harboring a novel heterozygous germline indel mutation in CARD11 (c.701-713delinsT), leading to one altered amino acid and a deletion of 4 others (p.His234_Lys238delinsLeu). Strikingly, affected members exhibit both moderate B cell lymphocytosis and atopic dermatitis/allergies. Ectopic expression of this CARD11 variant stimulated constitutive NF-κB activity in T cell lines, similar to other BENTA patient mutations. However, unlike other GOF mutants, this variant significantly impeded the ability of wild-type CARD11 to induce NF-κB activation following antigen receptor ligation. Patient lymphocytes display marked intrinsic defects in B cell differentiation and reduced T cell responsiveness in vitro. Collectively, these data imply that a single heterozygous CARD11 mutation can convey both GOF and DN signaling effects, manifesting in a blended BENTA phenotype with atopic features. Our findings further emphasize the importance of balanced CARD11 signaling for normal immune responses. |
format | Online Article Text |
id | pubmed-6299974 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-62999742019-01-07 A Unique Heterozygous CARD11 Mutation Combines Pathogenic Features of Both Gain- and Loss-of-Function Patients in a Four-Generation Family Desjardins, Marylin Arjunaraja, Swadhinya Stinson, Jeffrey R. Dorjbal, Batsukh Sundaresan, Janani Niemela, Julie Raffeld, Mark Matthews, Helen F. Wang, Angela Angelus, Pamela Su, Helen C. Mazer, Bruce D. Snow, Andrew L. Front Immunol Immunology CARD11 is a lymphocyte-specific scaffold molecule required for proper activation of B- and T-cells in response to antigen. Germline gain-of-function (GOF) mutations in the CARD11 gene cause a unique B cell lymphoproliferative disorder known as B cell Expansion with NF-κB and T cell Anergy (BENTA). In contrast, patients carrying loss-of-function (LOF), dominant negative (DN) CARD11 mutations present with severe atopic disease. Interestingly, both GOF and DN CARD11 variants cause primary immunodeficiency, with recurrent bacterial and viral infections, likely resulting from impaired adaptive immune responses. This report describes a unique four-generation family harboring a novel heterozygous germline indel mutation in CARD11 (c.701-713delinsT), leading to one altered amino acid and a deletion of 4 others (p.His234_Lys238delinsLeu). Strikingly, affected members exhibit both moderate B cell lymphocytosis and atopic dermatitis/allergies. Ectopic expression of this CARD11 variant stimulated constitutive NF-κB activity in T cell lines, similar to other BENTA patient mutations. However, unlike other GOF mutants, this variant significantly impeded the ability of wild-type CARD11 to induce NF-κB activation following antigen receptor ligation. Patient lymphocytes display marked intrinsic defects in B cell differentiation and reduced T cell responsiveness in vitro. Collectively, these data imply that a single heterozygous CARD11 mutation can convey both GOF and DN signaling effects, manifesting in a blended BENTA phenotype with atopic features. Our findings further emphasize the importance of balanced CARD11 signaling for normal immune responses. Frontiers Media S.A. 2018-12-12 /pmc/articles/PMC6299974/ /pubmed/30619304 http://dx.doi.org/10.3389/fimmu.2018.02944 Text en Copyright © 2018 Desjardins, Arjunaraja, Stinson, Dorjbal, Sundaresan, Niemela, Raffeld, Matthews, Wang, Angelus, Su, Mazer and Snow. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Desjardins, Marylin Arjunaraja, Swadhinya Stinson, Jeffrey R. Dorjbal, Batsukh Sundaresan, Janani Niemela, Julie Raffeld, Mark Matthews, Helen F. Wang, Angela Angelus, Pamela Su, Helen C. Mazer, Bruce D. Snow, Andrew L. A Unique Heterozygous CARD11 Mutation Combines Pathogenic Features of Both Gain- and Loss-of-Function Patients in a Four-Generation Family |
title | A Unique Heterozygous CARD11 Mutation Combines Pathogenic Features of Both Gain- and Loss-of-Function Patients in a Four-Generation Family |
title_full | A Unique Heterozygous CARD11 Mutation Combines Pathogenic Features of Both Gain- and Loss-of-Function Patients in a Four-Generation Family |
title_fullStr | A Unique Heterozygous CARD11 Mutation Combines Pathogenic Features of Both Gain- and Loss-of-Function Patients in a Four-Generation Family |
title_full_unstemmed | A Unique Heterozygous CARD11 Mutation Combines Pathogenic Features of Both Gain- and Loss-of-Function Patients in a Four-Generation Family |
title_short | A Unique Heterozygous CARD11 Mutation Combines Pathogenic Features of Both Gain- and Loss-of-Function Patients in a Four-Generation Family |
title_sort | unique heterozygous card11 mutation combines pathogenic features of both gain- and loss-of-function patients in a four-generation family |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299974/ https://www.ncbi.nlm.nih.gov/pubmed/30619304 http://dx.doi.org/10.3389/fimmu.2018.02944 |
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