A novel NFKB1 variant in a Japanese pedigree with common variable immunodeficiency.
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SUBMITTER: Nakatani N
PROVIDER: S-EPMC10957891 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
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A novel NFKB1 variant in a Japanese pedigree with common variable immunodeficiency.
Nakatani Naoko N Tamura Akihiro A Hanafusa Hiroaki H Nino Nanako N Yamamoto Nobuyuki N Awano Hiroyuki H Tanaka Yasuhiro Y Morisada Naoya N Uemura Suguru S Saito Atsuro A Hasegawa Daiichiro D Nozu Kandai K Kosaka Yoshiyuki Y
Human genome variation 20240322 1
Recently, heterozygous loss-of-function NFKB1 variants were identified as the primary cause of common variable immunodeficiency (CVID) in the European population. However, pathogenic NFKB1 variants have never been reported in the Japanese population. We present a 29-year-old Japanese woman with CVID. A novel variant, c.136 C > T, p.(Gln46*), was identified in NFKB1. Her mother and daughter carried the same variant, demonstrating the first Japanese pedigree with an NFKB1 pathogenic variant. ...[more]
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Project description:NFKB1 haploinsufficiengcy was first described in 2015 in three families with common variable immunodeficiency (CVID), presenting heterogeneously with symptoms of increased infectious susceptibility, skin lesions, malignant lymphoproliferation and autoimmunity. The described mutations all led to a rapid degradation of the mutant protein, resulting in a p50 haploinsufficient state. Since then, more than 50 other mutations have been reported, located throughout different domains of NFKB1 with the majority situated in the N-terminal Rel homology domain (RHD). The clinical spectrum has also expanded with possible disease manifestations in almost any organ system. In silico prediction tools are often used to estimate the pathogenicity of NFKB1 variants but to prove causality between disease and genetic findings, further downstream functional validation is required. In this report, we studied 2 families with CVID and two novel variants in NFKB1 (c.1638-2A>G and c.787G>C). Both mutations affected mRNA and/or protein expression of NFKB1 and resulted in excessive NLRP3 inflammasome activation in patient macrophages and upregulated interferon stimulated gene expression. Protein-protein interaction analysis demonstrated a loss of interaction with NFKB1 interaction partners for the p.V263L mutation. In conclusion, we proved pathogenicity of two novel variants in NFKB1 in two families with CVID characterized by variable and incomplete penetrance.
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