Loss of B cells in patients with heterozygous mutations in IKAROS

Hye Sun Kuehn, Bertrand Boisson, Charlotte Cunningham-Rundles, Janine Reichenbach, Asbjørg Stray-Pedersen, Erwin W. Gelfand, Patrick Maffucci, Keith R. Pierce, Jordan K. Abbott, Karl V. Voelkerding, Sarah T. South, Nancy H. Augustine, Jeana S. Bush, William K. Dolen, Betty B. Wray, Yuval Itan, Aurelie Cobat, Hanne Sørmo Sorte, Sundar Ganesan, Seraina PraderThomas B. Martins, Monica G. Lawrence, Jordan S. Orange, Katherine R. Calvo, Julie E. Niemela, Jean Laurent Casanova, Thomas A. Fleisher, Harry R. Hill, Attila Kumánovics, Mary Ellen Conley, Sergio D. Rosenzweig

Research output: Contribution to journalArticle

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Abstract

BACKGROUND Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobilityshift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.)

Original languageEnglish (US)
Pages (from-to)1032-1043
Number of pages12
JournalNew England Journal of Medicine
Volume374
Issue number11
DOIs
StatePublished - Mar 17 2016

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Common Variable Immunodeficiency
B-Lymphocytes
Mutation
Plasma Cells
Confocal Microscopy
Transcription Factors
Cell Count
Bone Marrow
Exome
Agammaglobulinemia
B-Lymphoid Precursor Cells
Comparative Genomic Hybridization
DNA
National Institutes of Health (U.S.)
Missense Mutation
Mutant Proteins
Amino Acid Substitution
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Causality
Immunoglobulins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kuehn, H. S., Boisson, B., Cunningham-Rundles, C., Reichenbach, J., Stray-Pedersen, A., Gelfand, E. W., ... Rosenzweig, S. D. (2016). Loss of B cells in patients with heterozygous mutations in IKAROS. New England Journal of Medicine, 374(11), 1032-1043. https://doi.org/10.1056/NEJMoa1512234

Loss of B cells in patients with heterozygous mutations in IKAROS. / Kuehn, Hye Sun; Boisson, Bertrand; Cunningham-Rundles, Charlotte; Reichenbach, Janine; Stray-Pedersen, Asbjørg; Gelfand, Erwin W.; Maffucci, Patrick; Pierce, Keith R.; Abbott, Jordan K.; Voelkerding, Karl V.; South, Sarah T.; Augustine, Nancy H.; Bush, Jeana S.; Dolen, William K.; Wray, Betty B.; Itan, Yuval; Cobat, Aurelie; Sorte, Hanne Sørmo; Ganesan, Sundar; Prader, Seraina; Martins, Thomas B.; Lawrence, Monica G.; Orange, Jordan S.; Calvo, Katherine R.; Niemela, Julie E.; Casanova, Jean Laurent; Fleisher, Thomas A.; Hill, Harry R.; Kumánovics, Attila; Conley, Mary Ellen; Rosenzweig, Sergio D.

In: New England Journal of Medicine, Vol. 374, No. 11, 17.03.2016, p. 1032-1043.

Research output: Contribution to journalArticle

Kuehn, HS, Boisson, B, Cunningham-Rundles, C, Reichenbach, J, Stray-Pedersen, A, Gelfand, EW, Maffucci, P, Pierce, KR, Abbott, JK, Voelkerding, KV, South, ST, Augustine, NH, Bush, JS, Dolen, WK, Wray, BB, Itan, Y, Cobat, A, Sorte, HS, Ganesan, S, Prader, S, Martins, TB, Lawrence, MG, Orange, JS, Calvo, KR, Niemela, JE, Casanova, JL, Fleisher, TA, Hill, HR, Kumánovics, A, Conley, ME & Rosenzweig, SD 2016, 'Loss of B cells in patients with heterozygous mutations in IKAROS', New England Journal of Medicine, vol. 374, no. 11, pp. 1032-1043. https://doi.org/10.1056/NEJMoa1512234
Kuehn HS, Boisson B, Cunningham-Rundles C, Reichenbach J, Stray-Pedersen A, Gelfand EW et al. Loss of B cells in patients with heterozygous mutations in IKAROS. New England Journal of Medicine. 2016 Mar 17;374(11):1032-1043. https://doi.org/10.1056/NEJMoa1512234
Kuehn, Hye Sun ; Boisson, Bertrand ; Cunningham-Rundles, Charlotte ; Reichenbach, Janine ; Stray-Pedersen, Asbjørg ; Gelfand, Erwin W. ; Maffucci, Patrick ; Pierce, Keith R. ; Abbott, Jordan K. ; Voelkerding, Karl V. ; South, Sarah T. ; Augustine, Nancy H. ; Bush, Jeana S. ; Dolen, William K. ; Wray, Betty B. ; Itan, Yuval ; Cobat, Aurelie ; Sorte, Hanne Sørmo ; Ganesan, Sundar ; Prader, Seraina ; Martins, Thomas B. ; Lawrence, Monica G. ; Orange, Jordan S. ; Calvo, Katherine R. ; Niemela, Julie E. ; Casanova, Jean Laurent ; Fleisher, Thomas A. ; Hill, Harry R. ; Kumánovics, Attila ; Conley, Mary Ellen ; Rosenzweig, Sergio D. / Loss of B cells in patients with heterozygous mutations in IKAROS. In: New England Journal of Medicine. 2016 ; Vol. 374, No. 11. pp. 1032-1043.
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abstract = "BACKGROUND Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10{\%} of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobilityshift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.)",
author = "Kuehn, {Hye Sun} and Bertrand Boisson and Charlotte Cunningham-Rundles and Janine Reichenbach and Asbj{\o}rg Stray-Pedersen and Gelfand, {Erwin W.} and Patrick Maffucci and Pierce, {Keith R.} and Abbott, {Jordan K.} and Voelkerding, {Karl V.} and South, {Sarah T.} and Augustine, {Nancy H.} and Bush, {Jeana S.} and Dolen, {William K.} and Wray, {Betty B.} and Yuval Itan and Aurelie Cobat and Sorte, {Hanne S{\o}rmo} and Sundar Ganesan and Seraina Prader and Martins, {Thomas B.} and Lawrence, {Monica G.} and Orange, {Jordan S.} and Calvo, {Katherine R.} and Niemela, {Julie E.} and Casanova, {Jean Laurent} and Fleisher, {Thomas A.} and Hill, {Harry R.} and Attila Kum{\'a}novics and Conley, {Mary Ellen} and Rosenzweig, {Sergio D.}",
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TY - JOUR

T1 - Loss of B cells in patients with heterozygous mutations in IKAROS

AU - Kuehn, Hye Sun

AU - Boisson, Bertrand

AU - Cunningham-Rundles, Charlotte

AU - Reichenbach, Janine

AU - Stray-Pedersen, Asbjørg

AU - Gelfand, Erwin W.

AU - Maffucci, Patrick

AU - Pierce, Keith R.

AU - Abbott, Jordan K.

AU - Voelkerding, Karl V.

AU - South, Sarah T.

AU - Augustine, Nancy H.

AU - Bush, Jeana S.

AU - Dolen, William K.

AU - Wray, Betty B.

AU - Itan, Yuval

AU - Cobat, Aurelie

AU - Sorte, Hanne Sørmo

AU - Ganesan, Sundar

AU - Prader, Seraina

AU - Martins, Thomas B.

AU - Lawrence, Monica G.

AU - Orange, Jordan S.

AU - Calvo, Katherine R.

AU - Niemela, Julie E.

AU - Casanova, Jean Laurent

AU - Fleisher, Thomas A.

AU - Hill, Harry R.

AU - Kumánovics, Attila

AU - Conley, Mary Ellen

AU - Rosenzweig, Sergio D.

PY - 2016/3/17

Y1 - 2016/3/17

N2 - BACKGROUND Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobilityshift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.)

AB - BACKGROUND Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobilityshift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.)

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