Unraveling NEMO: how a single gene shapes immune resilience and rare disease
image: Study selection flowchart for systematic review of IKBKG mutations. A PRISMA-based flow diagram illustrating the selection process for studies included in the systematic review. From an initial 2,467 records identified across six major databases, 144 studies were ultimately included after removing duplicates and applying strict eligibility criteria based on clinical data relevance and mutation reporting.
Credit: Genes & Diseases
A new study has traced the genetic roots of several rare and complex disorders to mutations in a single critical gene: IKBKG, also known as NEMO. By analyzing 564 documented cases, researchers uncovered how different mutations in this gene are linked to a variety of syndromes—including incontinentia pigmenti (IP), anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), and other immune-related conditions. The findings highlight the wide-ranging symptoms caused by impaired NF-κB signaling, ranging from skin abnormalities to life-threatening infections. This systematic mapping of gene variants and disease outcomes may reshape clinical diagnosis and open doors to more targeted treatment strategies.
The NF-κB signaling pathway plays a pivotal role in how our bodies fight infection, heal, and regulate inflammation. At the heart of this pathway is the NEMO protein, encoded by the IKBKG gene. When this gene malfunctions, it can lead to a diverse spectrum of diseases—from pigment changes and dental anomalies to severe immunodeficiency (ID) and inflammation. The challenge for clinicians is that these mutations often present in vastly different ways across patients, sometimes with subtle or overlapping symptoms. Due to these complexities, there is an urgent need for a comprehensive clinical map of IKBKG mutations to improve early diagnosis and personalized care.
On January 12, 2025, researchers from Chongqing Medical University published a comprehensive review (DOI: 10.1016/j.gendis.2025.101531) in Genes & Diseases, offering one of the most detailed clinical landscapes of IKBKG mutations to date. Analyzing 144 studies and 564 cases, the team systematically classified how specific genetic mutations correspond to a variety of rare disorders—including incontinentia pigmenti (IP), anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), ID, and the recently identified NDAS. By drawing connections between genetic variations and disease severity, the study equips clinicians with a clearer diagnostic framework for recognizing these complex conditions rooted in NF-κB dysfunction.
The research revealed a striking range of disease presentations driven by IKBKG mutations. Most cases were diagnosed as IP (78%), followed by EDA-ID (15.8%), ID (5.0%), and NDAS (1.2%). Female patients predominantly had IP, while the other syndromes mainly affected males. Common symptoms ranged from skin pigmentation abnormalities and dental defects to recurrent, severe infections and systemic inflammation.
The study found that the zinc finger (ZF) domain of IKBKG was especially prone to disease-causing mutations, many of which led to the most severe outcomes. Variants such as E390RfsX5, H413R, and X420W were associated with multi-organ involvement and high phenotype scores. Notably, some mutations—like E390RfsX5—appeared across multiple disease categories, complicating diagnosis and treatment decisions. Beyond symptom mapping, the study identified patterns in infection susceptibility. Mycobacteria and Streptococcus were frequent culprits, and immunoglobulin abnormalities—especially IgG and IgM deficiencies—were common among EDA-ID and ID patients. The detailed genotype–phenotype correlations developed in this review offer a roadmap for clinicians navigating ambiguous or overlapping presentations.
“This research sheds light on a notoriously elusive group of disorders,” said Dr. Yuan Ding, senior author of the study. “What makes IKBKG-related conditions so challenging is their variability—two patients with the same mutation can present entirely different symptoms. Our findings offer a much-needed clinical guide to help physicians recognize these cases earlier, improve outcomes, and reduce diagnostic delays, especially in children.”
The study offers a practical foundation for precision diagnostics in rare ID and inflammatory diseases. By linking specific IKBKG mutations to clinical outcomes, healthcare providers can better anticipate disease progression and tailor treatments—whether through immunoglobulin therapy, stem-cell transplantation, or emerging gene-editing technologies. The review also underscores the urgency of recognizing underdiagnosed cases, especially in infants and young children with unusual infections or skin and dental anomalies. As gene therapy research accelerates, this comprehensive mutation map may serve as a reference point for designing mutation-specific interventions, bringing hope to patients and families affected by these complex syndromes.
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References
DOI
Original Source URL
https://doi.org/10.1016/j.gendis.2025.101531
About Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Emphasis will be placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases.