Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency.
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.
Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany.
Manfred
M
Fliegauf
Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
Vanessa L
VL
Bryant
Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany.
Natalie
N
Frede
Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
Charlotte
C
Slade
Department of Virology and Immunology, Auckland City Hospital, Auckland 1023, New Zealand.
See-Tarn
ST
Woon
School of Biological Sciences, University of Auckland, Auckland 1142, New Zealand.
Klaus
K
Lehnert
Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany.
Sandra
S
Winzer
Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany.
Alla
A
Bulashevska
Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
Thomas
T
Scerri
Auckland Cancer Society Research Centre and Molecular Medicine and Pathology Department, University of Auckland, Auckland 1142, New Zealand.
Euphemia
E
Leung
Department of Clinical Immunology, Auckland City Hospital, Auckland 1023, New Zealand.
Anthony
A
Jordan
Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany.
Baerbel
B
Keller
Department of Pediatrics, Jeroen Bosch Hospital, 's-Hertogenbosch 5200 ME, the Netherlands.
Esther
E
de Vries
BGI-Shenzhen, Shenzhen, 518083, China.
Hongzhi
H
Cao
BGI-Shenzhen, Shenzhen, 518083, China.
Fang
F
Yang
NCBI, NIH, Department of Health and Human Services, Bethesda, MD 20894, USA.
Alejandro A
AA
Schäffer
Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany.
Klaus
K
Warnatz
Auckland Cancer Society Research Centre and Molecular Medicine and Pathology Department, University of Auckland, Auckland 1142, New Zealand.
Peter
P
Browett
Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Parkville, VIC 3050, Australia; Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia.
Jo
J
Douglass
Department of Virology and Immunology, Auckland City Hospital, Auckland 1023, New Zealand.
Rohan V
RV
Ameratunga
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen 6525 HP, the Netherlands.
Jos W M
JW
van der Meer
Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg 79108, Germany; Institute of Immunity and Transplantation, University College London, London WC1E 6BT, UK. Electronic address: bodo.grimbacher@uniklinik-freiburg.de.
Bodo
B
Grimbacher
D001315:Australia; D001483:Base Sequence; D015153:Blotting, Western; D017074:Common Variable Immunodeficiency / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D059472:Exome / Q000235:genetics; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D052002:NF-kappa B p50 Subunit / Q000235:genetics*; D009426:Netherlands; D009520:New Zealand; D017422:Sequence Analysis, DNA
D017931:DNA Primers; D052002:NF-kappa B p50 Subunit