TY - JOUR
T1 - Novel hypomorphic mutation in IKBKG impairs NEMO-ubiquitylation causing ectodermal dysplasia, immunodeficiency, incontinentia pigmenti, and immune thrombocytopenic purpura
AU - Ramírez-Alejo, Noé
AU - Alcántara-Montiel, Julio C.
AU - Yamazaki-Nakashimada, Marco
AU - Duran-McKinster, Carola
AU - Valenzuela-León, Paola
AU - Rivas-Larrauri, Francisco
AU - Cedillo-Barrón, Leticia
AU - Hernández-Rivas, Rosaura
AU - Santos-Argumedo, Leopoldo
N1 - Funding Information:
We thank the patient and his family for their trust. We thank Jean-Laurent Casanova, Stéphanie Boisson-Dupuis, and Jacinta Bustamante for the donation of EBV-B cells from patient with complete NEMO deficiency, which were used as negative controls in these experiments. This work was supported by the Instituto de Ciencia y Tecnología del Distrito Federal (Grant PICSA12-157 ) and the Consejo Nacional de Ciencia y Tecnología (Grant Salud-202111 ). NRA and JCAM are supported by doctoral scholarships 456878 and 233351 from the Consejo Nacional de Ciencia y Tecnología. The authors acknowledge Julio García Cordero, Dulce Delgadillo Alvarez, Victor Hugo Rosales García, and Héctor Romero Ramírez for technical assistance.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - NF-κB essential modulator (NEMO) is a component of the IKK complex, which participates in the activation of the NF-κB pathway. Hypomorphic mutations in the IKBKG gene result in different forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males without affecting carrier females. Here, we describe a hypomorphic and missense mutation, designated c.916 G > A (p.D306N), which affects our patient, his mother, and his sister. This mutation did not affect NEMO expression; however, an immunoprecipitation assay revealed reduced ubiquitylation upon CD40-stimulation in the patient's cells. Functional studies have demonstrated reduced phosphorylation and degradation of IκBα, affecting NF-κB recruitment into the nucleus. The patient presented with clinical features of ectodermal dysplasia, immunodeficiency, and immune thrombocytopenic purpura, the latter of which has not been previously reported in a patient with NEMO deficiency. His mother and sister displayed incontinentia pigmenti indicating that, in addition to amorphic mutations, hypomorphic mutations in NEMO can affect females.
AB - NF-κB essential modulator (NEMO) is a component of the IKK complex, which participates in the activation of the NF-κB pathway. Hypomorphic mutations in the IKBKG gene result in different forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males without affecting carrier females. Here, we describe a hypomorphic and missense mutation, designated c.916 G > A (p.D306N), which affects our patient, his mother, and his sister. This mutation did not affect NEMO expression; however, an immunoprecipitation assay revealed reduced ubiquitylation upon CD40-stimulation in the patient's cells. Functional studies have demonstrated reduced phosphorylation and degradation of IκBα, affecting NF-κB recruitment into the nucleus. The patient presented with clinical features of ectodermal dysplasia, immunodeficiency, and immune thrombocytopenic purpura, the latter of which has not been previously reported in a patient with NEMO deficiency. His mother and sister displayed incontinentia pigmenti indicating that, in addition to amorphic mutations, hypomorphic mutations in NEMO can affect females.
KW - Ectodermal dysplasia
KW - Immune thrombocytopenic purpura
KW - Immunodeficiency
KW - NEMO
UR - http://www.scopus.com/inward/record.url?scp=84938090206&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84938090206&partnerID=8YFLogxK
U2 - 10.1016/j.clim.2015.06.007
DO - 10.1016/j.clim.2015.06.007
M3 - Article
C2 - 26117626
AN - SCOPUS:84938090206
SN - 1521-6616
VL - 160
SP - 163
EP - 171
JO - Clinical Immunology
JF - Clinical Immunology
IS - 2
ER -