EDA-ID and IP, two faces of the same coin: how the same IKBKG/NEMO mutation affecting the NF-κB pathway can cause immunodeficiency and/or inflammation.
Anhidrotic Ectodermal Dysplasia with ImmunoDeficiency (EDA-ID, OMIM 300291) and Incontinentia Pigmenti (IP, OMIM 308300) are two rare diseases, caused by mutations of the IKBKG/NEMO gene. The protein NEMO/IKKγ is essential for the NF-κB activation pathway, involved in a variety of physiological and cellular processes, such as immunity, inflammation, cell proliferation, and survival. A wide spectrum of IKBKG/NEMO mutations have been identified so far, and, on the basis of their effect on NF-κB activation, they are considered hypomorphic or amorphic (loss of function) mutations. IKBKG/NEMO hypomorphic mutations, reducing but not abolishing NF-κB activation, have been identified in EDA-ID and IP patients. Instead, the amorphic mutations, abolishing NF-κB activation by complete IKBKG/NEMO gene silencing, cause only IP. Here, we present an overview of IKBKG/NEMO mutations in EDA-ID and IP patients and describe similarities and differences between the clinical/immunophenotypic and genetic aspects, highlighting any T and B lymphocyte defect, and paying particular attention to the cellular and molecular defects that underlie the pathogenesis of both diseases.
a Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' , IGB-CNR, Naples , Italy.
Francesca
F
Fusco
a Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' , IGB-CNR, Naples , Italy.
Alessandra
A
Pescatore
a Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' , IGB-CNR, Naples , Italy.
Matilde Immacolata
MI
Conte
b Fondazione SDN IRCCS , Naples , Italy.
Peppino
P
Mirabelli
a Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' , IGB-CNR, Naples , Italy.|c University of Basilicata , Potenza , Italy.
Mariateresa
M
Paciolla
a Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' , IGB-CNR, Naples , Italy.
Elio
E
Esposito
c University of Basilicata , Potenza , Italy.
Maria Brigida
MB
Lioi
a Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' , IGB-CNR, Naples , Italy.|b Fondazione SDN IRCCS , Naples , Italy.
Matilde Valeria
MV
Ursini
D000818:Animals; D004476:Ectodermal Dysplasia / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism*; D056726:Genetic Association Studies; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism*; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism*; D007184:Incontinentia Pigmenti / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D010641:Phenotype; D000081207:Primary Immunodeficiency Diseases; D015398:Signal Transduction
C491731:IKBKG protein, human; D016328:NF-kappa B; D051550:I-kappa B Kinase
IKBKG/NEMO mutations; NF-κB; immunodeficiency; inflammation; mutation sequence analysis