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J Allergy Clin Immunol. 2018 Mar;141(3):1060-1073.e3. doi: 10.1016/j.jaci.2017.05.030. Epub 2017 Jun 17.

Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency.

Author information

1
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
2
Division of Immunology and Infectious Diseases, Department of Pediatrics, Bambino Gesù Children's Hospital, Rome, and University of Rome Tor Vergata, Rome, Italy.
3
Department of Pediatrics, Tohoku University, Tohoku, Japan.
4
Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
5
Division of Allergy, Immunology, and Bone Marrow Transplantation, University of California, San Francisco, Calif.
6
Immunology Service, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina.
7
Department of Pediatrics, Gifu University, Gifu, Japan.
8
Department of Pediatrics, Kyoto University, Kyoto, Japan.
9
Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.
10
Immunodeficiency Diagnosis and Treatment Program, Department of Pediatrics, National Jewish Health, Denver, Colo.
11
Merck Research Laboratories Boston, Boston, Mass.
12
Division of Allergy, Asthma, and Immunology, Children's Hospital of Michigan, Detroit, Mich.
13
Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital, Paris Descartes University, Paris, France.
14
Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital, Paris Descartes University, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY.
15
Department of Pediatric Hematology and Oncology, Dr von Hauner University Children's Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany.
16
Department of Pediatrics, University of Washington School of Medicine, Seattle, Wash.
17
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass. Electronic address: raif.geha@childrens.harvard.edu.

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 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.

OBJECTIVE:

We sought to establish genotype-phenotype correlation in patients with AD EDA-ID.

METHODS:

A 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.

RESULTS:

Disease 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.

CONCLUSIONS:

IκBα 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.

KEYWORDS:

Ectodermal dysplasia with immune deficiency; NF-κB inhibitor α; canonical nuclear factor κB pathway; hematopoietic stem cell transplantation; lymphorganogenesis; noncanonical nuclear factor κB pathway

PMID:
28629746
PMCID:
PMC5733640
[Available on 2019-03-01]
DOI:
10.1016/j.jaci.2017.05.030

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