Defective Function of Inhibitor of κB Kinase Subunit Beta Associated With Multiple Immune-Mediated Disorders

Area of Science:

• Genetics
• Immunology
• Molecular Biology

Background:

• Abnormal nuclear factor-kappa B (NF-κB) activity is linked to immune disorders.
• The co-occurrence of vitiligo, Addison's disease, and granuloma annulare suggests a shared genetic etiology.

Purpose of the Study:

• To investigate the genetic basis for the co-occurrence of vitiligo, Addison's disease, and granuloma annulare in a patient.
• To elucidate the functional impact of identified genetic variants on NF-κB signaling.

Main Methods:

• Whole-exome sequencing to identify genetic variants.
• Immunoblotting and luciferase reporter assays to assess protein function.
• Gene expression analysis to evaluate NF-κB target gene regulation.

Main Results:

• A heterozygous splice-site variant (c.1364+1G>A, p.Met455fsTer1) was identified in IKBKB, encoding Inhibitor of κB kinase subunit beta (IKKβ).
• The IKBKB variant resulted in a truncated IKKβ protein with reduced activity, indicating a loss-of-function.
• NF-κB-dependent gene expression and p105/p50 levels were decreased in cells with the IKBKB variant.

Conclusions:

• A loss-of-function mutation in IKBKB disrupts NF-κB signaling.
• This disruption may underlie the co-occurrence of autoimmune diseases like vitiligo, Addison's disease, and granuloma annulare.