1. Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency
- Author
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Petersheim, Daniel, Massaad, Michel J, Lee, Saetbyul, Scarselli, Alessia, Cancrini, Caterina, Moriya, Kunihiko, Sasahara, Yoji, Lankester, Arjan C, Dorsey, Morna, Di Giovanni, Daniela, Bezrodnik, Liliana, Ohnishi, Hidenori, Nishikomori, Ryuta, Tanita, Kay, Kanegane, Hirokazu, Morio, Tomohiro, Gelfand, Erwin W, Jain, Ashish, Secord, Elizabeth, Picard, Capucine, Casanova, Jean-Laurent, Albert, Michael H, Torgerson, Troy R, and Geha, Raif S
- Subjects
Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Carrier Proteins ,Chemokine CCL20 ,Ectodermal Dysplasia ,Genetic Diseases ,X-Linked ,Genotype ,HEK293 Cells ,Humans ,Immunologic Deficiency Syndromes ,Intercellular Adhesion Molecule-1 ,Interleukin-6 ,NF-KappaB Inhibitor alpha ,NF-kappa B p52 Subunit ,Point Mutation ,Primary Immunodeficiency Diseases ,Proto-Oncogene Mas ,Signal Transduction ,Ectodermal dysplasia with immune deficiency ,NF-kappa B inhibitor alpha ,canonical nuclear factor kappa B pathway ,noncanonical nuclear factor kappa B pathway ,lymphorganogenesis ,hematopoietic stem cell transplantation ,NF-κB inhibitor α ,canonical nuclear factor κB pathway ,noncanonical nuclear factor κB pathway ,Immunology ,Allergy - Abstract
BackgroundAutosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in IκBα that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor κ light chain enhancer of activated B cells (NF-κB) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in IκBα have impaired noncanonical NF-κB activity and defective lymphorganogenesis.ObjectiveWe sought to establish genotype-phenotype correlation in patients with AD EDA-ID.MethodsA disease severity scoring system was devised. Stability of IκBα mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-κB signaling in skin-derived fibroblasts.ResultsDisease severity was greater in patients with IκBα point mutations than in those with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-κB-dependent IL-6 secretion and upregulation of the NF-κB subunit 2/p100 and RELB proto-oncogene, NF-κB subunit (RelB) components of the noncanonical NF-κB pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-κB-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus α-lymphotoxin β receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations.ConclusionsIκBα point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-κB activity in patients with AD EDA-ID.
- Published
- 2018