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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.; Geha, Raif S. (2018): Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. In: Journal of Allergy and Clinical Immunology, Vol. 141, No. 3: pp. 1060-1073
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Abstract

Background: Autosomal 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 I kappa B alpha that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor kappa light chain enhancer of activated B cells (NF-kappa B) 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 I kappa B alpha have impaired noncanonical NF-kappa B activity and defective lymphorganogenesis. Objective: We sought to establish genotype-phenotype correlation in patients with AD EDA-ID. Methods: A disease severity scoring system was devised. Stability of I kappa B alpha mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-kappa B signaling in skin-derived fibroblasts. Results: Disease severity was greater in patients with IkBa point mutations than in those with truncation mutations. IkBa point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-kappa B-dependent IL-6 secretion and upregulation of the NF-kappa B subunit 2/p100 and RELB proto-oncogene, NF-kappa B subunit (RelB) components of the noncanonical NF-kappa B pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-kappa B-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 alpha-lymphotoxin beta receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations. Conclusions: I kappa B alpha 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-kappa B activity in patients with AD EDA-ID.