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A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency.

ABSTRACT: X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the gene encoding NEMO/IKKgamma, the regulatory subunit of the IkappaB kinase (IKK) complex. IKK normally phosphorylates the IkappaB-inhibitors of NF-kappaB at specific serine residues, thereby promoting their ubiquitination and degradation by the proteasome. This allows NF-kappaB complexes to translocate into the nucleus where they activate their target genes. Here, we describe an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous missense mutation at serine 32 of IkappaBalpha. This mutation is gain-of-function, as it enhances the inhibitory capacity of IkappaBalpha by preventing its phosphorylation and degradation, and results in impaired NF-kappaB activation. The developmental, immunologic, and infectious phenotypes associated with hypomorphic NEMO and hypermorphic IKBA mutations largely overlap and include EDA, impaired cellular responses to ligands of TIR (TLR-ligands, IL-1beta, and IL-18), and TNFR (TNF-alpha, LTalpha1/beta2, and CD154) superfamily members and severe bacterial diseases. However, AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell immunodeficiency. Despite a marked blood lymphocytosis, there are no detectable memory T cells in vivo, and naive T cells do not respond to CD3-TCR activation in vitro. Our report highlights both the diversity of genotypes associated with EDA-ID and the diversity of immunologic phenotypes associated with mutations in different components of the NF-kappaB signaling pathway.

SUBMITTER: Courtois G

PROVIDER: S-EPMC198529 | biostudies-literature | 2003 Oct

REPOSITORIES: biostudies-literature

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A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency.

Courtois Gilles G Smahi Asma A Reichenbach Janine J Döffinger Rainer R Cancrini Caterina C Bonnet Marion M Puel Anne A Chable-Bessia Christine C Yamaoka Shoji S Feinberg Jacqueline J Dupuis-Girod Sophie S Bodemer Christine C Livadiotti Susanna S Novelli Francesco F Rossi Paolo P Fischer Alain A Israël Alain A Munnich Arnold A Le Deist Françoise F Casanova Jean-Laurent JL

The Journal of clinical investigation 20031001 7

X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the gene encoding NEMO/IKKgamma, the regulatory subunit of the IkappaB kinase (IKK) complex. IKK normally phosphorylates the IkappaB-inhibitors of NF-kappaB at specific serine residues, thereby promoting their ubiquitination and degradation by the proteasome. This allows NF-kappaB complexes to translocate into the nucleus where they activate their target genes. Here, we describe an au ...[more]

PMID: 14523047

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Project description: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?B? that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor ? light chain enhancer of activated B cells (NF-?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?B? have impaired noncanonical NF-?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?B? mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-?B signaling in skin-derived fibroblasts. RESULTS:Disease severity was greater in patients with I?B? point mutations than in those with truncation mutations. I?B? point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-?B-dependent IL-6 secretion and upregulation of the NF-?B subunit 2/p100 and RELB proto-oncogene, NF-?B subunit (RelB) components of the noncanonical NF-?B pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-?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 ?-lymphotoxin ? receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations. CONCLUSIONS:I?B? 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-?B activity in patients with AD EDA-ID.

Project description:BACKGROUND:Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ channels is an essential signaling pathway in many cell types. Ca2+ release-activated Ca2+ channels are formed by ORAI1, ORAI2, and ORAI3 proteins and activated by stromal interaction molecule (STIM) 1 and STIM2. Mutations in the ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and nonimmunologic symptoms. OBJECTIVE:We performed molecular and immunologic analysis of patients with CID, anhidrosis, and ectodermal dysplasia of unknown etiology. METHODS:We performed DNA sequencing of the ORAI1 gene, modeling of mutations on ORAI1 crystal structure, analysis of ORAI1 mRNA and protein expression, SOCE measurements, immunologic analysis of peripheral blood lymphocyte populations by using flow cytometry, and histologic and ultrastructural analysis of patient tissues. RESULTS:We identified 3 novel autosomal recessive mutations in ORAI1 in unrelated kindreds with CID, autoimmunity, ectodermal dysplasia with anhidrosis, and muscular dysplasia. The patients were homozygous for p.V181SfsX8, p.L194P, and p.G98R mutations in the ORAI1 gene that suppressed ORAI1 protein expression and SOCE in the patients' lymphocytes and fibroblasts. In addition to impaired T-cell cytokine production, ORAI1 mutations were associated with strongly reduced numbers of invariant natural killer T and regulatory T (Treg) cells and altered composition of γδ T-cell and natural killer cell subsets. CONCLUSION:ORAI1 null mutations are associated with reduced numbers of invariant natural killer T and Treg cells that likely contribute to the patients' immunodeficiency and autoimmunity. ORAI1-deficient patients have dental enamel defects and anhidrosis, representing a new form of anhidrotic ectodermal dysplasia with immunodeficiency that is distinct from previously reported patients with anhidrotic ectodermal dysplasia with immunodeficiency caused by mutations in the nuclear factor κB signaling pathway (IKBKG and NFKBIA).

Dataset Information

A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency.

Publications

A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency.

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