BACKGROUND: Hypomorphic mutations in the nuclear factor-κB (NF-κB) essential modulator (NEMO) gene result in a variable syndrome of somatic and immunologic abnormalities. Clinically relevant genotype-phenotype associations are essential to understanding this complex disease. OBJECTIVE: To study 2 unrelated boys with novel NEMO mutations altering codon 223 for similarity in phenotype in consideration of potential genotype-phenotype associations. METHODS: Clinical and laboratory features, including cell counts, immunoglobulin quantity and quality, natural killer cell cytotoxicity, and Toll-like and tumor necrosis factor receptor signaling, were evaluated. Because both mutations affected NEMO codon 223 and were novel, consideration was given to new potential genotype-phenotype associations. RESULTS: Both patients were diagnosed as having hypohidrotic ectodermal dysplasia and had severe or recurrent infections. One had recurrent sinopulmonary infections and the other necrotizing soft tissue methicillin-resistant Staphylococcus aureus infection and Streptococcus anginosus subdural empyema with bacteremia. NEMO gene sequence demonstrated a 3-nucleotide deletion (c.667_669delGAG) in one patient and a substitution (667G>A) in the other. These findings predict either the deletion of NEMO glutamic acid 223 or it being replaced with lysine, respectively. Both patients had normal serum IgG levels but poor specific antibodies. Natural killer cell cytotoxicity and Toll-like and tumor necrosis factor receptor signaling were also impaired. Serious bacterial infection did not occur in both patients after immunoglobulin replacement therapy. CONCLUSIONS: Two different novel mutations affecting NEMO glutamic acid 223 resulted in clinically relevant similar phenotypes, providing further evidence to support genotype-phenotype correlations in this disease. They suggest NEMO residue 223 is required for ectodermal development and immunity and is apparently dispensable for quantitative IgG production but may be required for specific antibody production.
BACKGROUND: Hypomorphic mutations in the nuclear factor-κB (NF-κB) essential modulator (NEMO) gene result in a variable syndrome of somatic and immunologic abnormalities. Clinically relevant genotype-phenotype associations are essential to understanding this complex disease. OBJECTIVE: To study 2 unrelated boys with novel NEMO mutations altering codon 223 for similarity in phenotype in consideration of potential genotype-phenotype associations. METHODS: Clinical and laboratory features, including cell counts, immunoglobulin quantity and quality, natural killer cell cytotoxicity, and Toll-like and tumor necrosis factor receptor signaling, were evaluated. Because both mutations affected NEMO codon 223 and were novel, consideration was given to new potential genotype-phenotype associations. RESULTS: Both patients were diagnosed as having hypohidrotic ectodermal dysplasia and had severe or recurrent infections. One had recurrent sinopulmonary infections and the other necrotizing soft tissue methicillin-resistant Staphylococcus aureus infection and Streptococcus anginosus subdural empyema with bacteremia. NEMO gene sequence demonstrated a 3-nucleotide deletion (c.667_669delGAG) in one patient and a substitution (667G>A) in the other. These findings predict either the deletion of NEMOglutamic acid 223 or it being replaced with lysine, respectively. Both patients had normal serum IgG levels but poor specific antibodies. Natural killer cell cytotoxicity and Toll-like and tumor necrosis factor receptor signaling were also impaired. Serious bacterial infection did not occur in both patients after immunoglobulin replacement therapy. CONCLUSIONS: Two different novel mutations affecting NEMOglutamic acid 223 resulted in clinically relevant similar phenotypes, providing further evidence to support genotype-phenotype correlations in this disease. They suggest NEMO residue 223 is required for ectodermal development and immunity and is apparently dispensable for quantitative IgG production but may be required for specific antibody production.
Authors: Jordan S Orange; Scott R Brodeur; Ashish Jain; Francisco A Bonilla; Lynda C Schneider; Roberto Kretschmer; Samuel Nurko; Wendy L Rasmussen; Julia R Köhler; Stephen E Gellis; Betsy M Ferguson; Jack L Strominger; Jonathan Zonana; Narayanaswamy Ramesh; Zuhair K Ballas; Raif S Geha Journal: J Clin Invest Date: 2002-06 Impact factor: 14.808
Authors: Owen M Siggs; Michael Berger; Philippe Krebs; Carrie N Arnold; Celine Eidenschenk; Christoph Huber; Elaine Pirie; Nora G Smart; Kevin Khovananth; Yu Xia; Gerald McInerney; Gunilla B Karlsson Hedestam; David Nemazee; Bruce Beutler Journal: Proc Natl Acad Sci U S A Date: 2010-01-28 Impact factor: 11.205
Authors: Eric P Hanson; Linda Monaco-Shawver; Laura A Solt; Lisa A Madge; Pinaki P Banerjee; Michael J May; Jordan S Orange Journal: J Allergy Clin Immunol Date: 2008-10-11 Impact factor: 10.793
Authors: Christoph B Geier; Alexander Piller; Angela Linder; Kai M T Sauerwein; Martha M Eibl; Hermann M Wolf Journal: PLoS One Date: 2015-07-17 Impact factor: 3.240