Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency

Manfred Fliegauf, Vanessa L Bryant, Natalie Frede, Charlotte Slade, See-Tarn Woon, Klaus Lehnert, Sandra Winzer, Alla Bulashevska, Thomas Scerri, Euphemia Leung, Anthony Jordan, Baerbel Keller, Esther de Vries, Hongzhi Cao, Fang Yang, Alejandro A Schäffer, Klaus Warnatz, Peter Browett, Jo Douglass, Rohan V AmeratungaJos W M van der Meer, Bodo Grimbacher

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In ∼90% of CVID-affected individuals, no genetic cause of the disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-κB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105ΔEx8) is degraded, but is not processed to p50ΔEx8. Altered NF-κB1 proteins were also undetectable in a German CVID-affected family with a heterozygous in-frame exon 9 skipping mutation (c.835+2T>G) and in a CVID-affected family from New Zealand with a heterozygous frameshift mutation (c.465dupA) in exon 7. Given that residual p105 and p50—translated from the non-mutated alleles—were normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.

Original languageEnglish
Pages (from-to)389-403
JournalAmerican Journal of Human Genetics
Volume97
Issue number3
DOIs
Publication statusPublished - 2015

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Common Variable Immunodeficiency
Haploinsufficiency
NF-kappa B p50 Subunit
Frameshift Mutation
Mutation
New Zealand

Cite this

Fliegauf, M., L Bryant, V., Frede, N., Slade, C., Woon, S-T., Lehnert, K., ... Grimbacher, B. (2015). Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency. American Journal of Human Genetics, 97(3), 389-403. https://doi.org/10.1016/j.ajhg.2015.07.008
Fliegauf, Manfred ; L Bryant, Vanessa ; Frede, Natalie ; Slade, Charlotte ; Woon, See-Tarn ; Lehnert, Klaus ; Winzer, Sandra ; Bulashevska, Alla ; Scerri, Thomas ; Leung, Euphemia ; Jordan, Anthony ; Keller, Baerbel ; de Vries, Esther ; Cao, Hongzhi ; Yang, Fang ; Schäffer, Alejandro A ; Warnatz, Klaus ; Browett, Peter ; Douglass, Jo ; Ameratunga, Rohan V ; van der Meer, Jos W M ; Grimbacher, Bodo. / Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency. In: American Journal of Human Genetics. 2015 ; Vol. 97, No. 3. pp. 389-403.
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title = "Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency",
abstract = "Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In ∼90{\%} of CVID-affected individuals, no genetic cause of the disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-κB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105ΔEx8) is degraded, but is not processed to p50ΔEx8. Altered NF-κB1 proteins were also undetectable in a German CVID-affected family with a heterozygous in-frame exon 9 skipping mutation (c.835+2T>G) and in a CVID-affected family from New Zealand with a heterozygous frameshift mutation (c.465dupA) in exon 7. Given that residual p105 and p50—translated from the non-mutated alleles—were normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.",
author = "Manfred Fliegauf and {L Bryant}, Vanessa and Natalie Frede and Charlotte Slade and See-Tarn Woon and Klaus Lehnert and Sandra Winzer and Alla Bulashevska and Thomas Scerri and Euphemia Leung and Anthony Jordan and Baerbel Keller and {de Vries}, Esther and Hongzhi Cao and Fang Yang and Sch{\"a}ffer, {Alejandro A} and Klaus Warnatz and Peter Browett and Jo Douglass and Ameratunga, {Rohan V} and {van der Meer}, {Jos W M} and Bodo Grimbacher",
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Fliegauf, M, L Bryant, V, Frede, N, Slade, C, Woon, S-T, Lehnert, K, Winzer, S, Bulashevska, A, Scerri, T, Leung, E, Jordan, A, Keller, B, de Vries, E, Cao, H, Yang, F, Schäffer, AA, Warnatz, K, Browett, P, Douglass, J, Ameratunga, RV, van der Meer, JWM & Grimbacher, B 2015, 'Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency', American Journal of Human Genetics, vol. 97, no. 3, pp. 389-403. https://doi.org/10.1016/j.ajhg.2015.07.008

Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency. / Fliegauf, Manfred; L Bryant, Vanessa; Frede, Natalie; Slade, Charlotte; Woon, See-Tarn; Lehnert, Klaus; Winzer, Sandra; Bulashevska, Alla; Scerri, Thomas; Leung, Euphemia; Jordan, Anthony; Keller, Baerbel; de Vries, Esther; Cao, Hongzhi; Yang, Fang; Schäffer, Alejandro A; Warnatz, Klaus; Browett, Peter; Douglass, Jo; Ameratunga, Rohan V; van der Meer, Jos W M; Grimbacher, Bodo.

In: American Journal of Human Genetics, Vol. 97, No. 3, 2015, p. 389-403.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency

AU - Fliegauf, Manfred

AU - L Bryant, Vanessa

AU - Frede, Natalie

AU - Slade, Charlotte

AU - Woon, See-Tarn

AU - Lehnert, Klaus

AU - Winzer, Sandra

AU - Bulashevska, Alla

AU - Scerri, Thomas

AU - Leung, Euphemia

AU - Jordan, Anthony

AU - Keller, Baerbel

AU - de Vries, Esther

AU - Cao, Hongzhi

AU - Yang, Fang

AU - Schäffer, Alejandro A

AU - Warnatz, Klaus

AU - Browett, Peter

AU - Douglass, Jo

AU - Ameratunga, Rohan V

AU - van der Meer, Jos W M

AU - Grimbacher, Bodo

N1 - Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2015

Y1 - 2015

N2 - Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In ∼90% of CVID-affected individuals, no genetic cause of the disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-κB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105ΔEx8) is degraded, but is not processed to p50ΔEx8. Altered NF-κB1 proteins were also undetectable in a German CVID-affected family with a heterozygous in-frame exon 9 skipping mutation (c.835+2T>G) and in a CVID-affected family from New Zealand with a heterozygous frameshift mutation (c.465dupA) in exon 7. Given that residual p105 and p50—translated from the non-mutated alleles—were normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.

AB - Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In ∼90% of CVID-affected individuals, no genetic cause of the disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-κB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105ΔEx8) is degraded, but is not processed to p50ΔEx8. Altered NF-κB1 proteins were also undetectable in a German CVID-affected family with a heterozygous in-frame exon 9 skipping mutation (c.835+2T>G) and in a CVID-affected family from New Zealand with a heterozygous frameshift mutation (c.465dupA) in exon 7. Given that residual p105 and p50—translated from the non-mutated alleles—were normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.

U2 - 10.1016/j.ajhg.2015.07.008

DO - 10.1016/j.ajhg.2015.07.008

M3 - Article

C2 - 26279205

VL - 97

SP - 389

EP - 403

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -