Non-Skewed X-inactivation Results in NF-κB Essential Modulator (NEMO) Δ-exon 5-autoinflammatory Syndrome (NEMO-NDAS) in a Female with Incontinentia Pigmenti.


Journal

Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137

Informations de publication

Date de publication:
12 Sep 2024
Historique:
received: 01 02 2024
accepted: 30 08 2024
medline: 12 9 2024
pubmed: 12 9 2024
entrez: 12 9 2024
Statut: epublish

Résumé

Genetic hypomorphic defects in X chromosomal IKBKG coding for the NF-κB essential modulator (NEMO) lead to ectodermal dysplasia and immunodeficiency in males and the skin disorder incontinentia pigmenti (IP) in females, respectively. NF-κB essential modulator (NEMO) Δ-exon 5-autoinflammatory syndrome (NEMO-NDAS) is a systemic autoinflammatory disease caused by alternative splicing and increased proportion of NEMO-Δex5. We investigated a female carrier presenting with IP and NEMO-NDAS due to non-skewed X-inactivation. IKBKG transcripts were quantified in peripheral blood mononuclear cells isolated from the patient, her mother, and healthy controls using RT-PCR and nanopore sequencing. Corresponding proteins were analyzed by western blotting and flow cytometry. Besides toll-like receptor (TLR) and tumor necrosis factor (TNF) signaling, the interferon signature, cytokine production and X-inactivation status were investigated. IP and autoinflammation with recurrent fever, oral ulcers, hepatitis, and neutropenia, but no immunodeficiency was observed in a female patient. Besides moderately reduced NEMO signaling function, type I interferonopathy, and elevated IL-18 and CXCL10 were found. She and her mother both carried the heterozygous variant c.613 C > T p.(Gln205*) in exon 5 of IKBKG previously reported in NEMO-deficient patients. However, X-inactivation was skewed in the mother, but not in the patient. Alternative splicing led to increased ratios of NEMO-Dex5 over full-length protein in peripheral blood cell subsets causing autoinflammation. Clinical symptoms partially resolved under treatment with TNF inhibitors. Non-skewed X-inactivation can lead to NEMO-NDAS in females with IP carrying hypomorphic IKBKG variants due to alternative splicing and increased proportions of NEMO-∆ex5.

Identifiants

pubmed: 39264518
doi: 10.1007/s10875-024-01799-2
pii: 10.1007/s10875-024-01799-2
doi:

Substances chimiques

I-kappa B Kinase EC 2.7.11.10
IKBKG protein, human 0
Cytokines 0

Types de publication

Journal Article Case Reports

Langues

eng

Sous-ensembles de citation

IM

Pagination

1

Informations de copyright

© 2024. The Author(s).

Références

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Auteurs

Jessica Eigemann (J)

Master's Program of Molecular Medicine, Medical Faculty of Ulm University, Ulm, Germany.
Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.

Ales Janda (A)

Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.

Catharina Schuetz (C)

Department of Pediatrics, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
German Center for Child and Adolescent Health (DZKJ), Partner Site Leipzig/Dresden, Dresden, Germany.

Min Ae Lee-Kirsch (MA)

Department of Pediatrics, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
German Center for Child and Adolescent Health (DZKJ), Partner Site Leipzig/Dresden, Dresden, Germany.

Ansgar Schulz (A)

Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
German Center for Child and Adolescent Health (DZKJ), Partner Site Ulm, Ulm, Germany.

Manfred Hoenig (M)

Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
German Center for Child and Adolescent Health (DZKJ), Partner Site Ulm, Ulm, Germany.

Ingrid Furlan (I)

Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.

Eva-Maria Jacobsen (EM)

Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.

Julia Zinngrebe (J)

Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.

Sarah Peters (S)

Department of Clinical Chemistry, Ulm University Medical Center, Ulm, Germany.

Cosima Drewes (C)

Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.

Reiner Siebert (R)

German Center for Child and Adolescent Health (DZKJ), Partner Site Ulm, Ulm, Germany.
Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.

Eva-Maria Rump (EM)

Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg - Hessen, Ulm, Germany.

Marita Führer (M)

Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg - Hessen, Ulm, Germany.

Myriam Lorenz (M)

Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.

Ulrich Pannicke (U)

Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.

Uwe Kölsch (U)

Department of Immunology, Labor Berlin - Charité Vivantes GmbH, Berlin, Germany.

Klaus-Michael Debatin (KM)

Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
German Center for Child and Adolescent Health (DZKJ), Partner Site Ulm, Ulm, Germany.

Horst von Bernuth (H)

Department of Immunology, Labor Berlin - Charité Vivantes GmbH, Berlin, Germany.
Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Nember of Freie Universität Berlin, Humboldt- Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin, Berlin Institute of Health (BIH), Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany.
German Center for Child and Adolescent Health (DZKJ), partner site Berlin, Berlin, Germany.

Klaus Schwarz (K)

German Center for Child and Adolescent Health (DZKJ), Partner Site Ulm, Ulm, Germany.
Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg - Hessen, Ulm, Germany.
Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.

Kerstin Felgentreff (K)

Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany. kerstin.felgentreff@uniklinik-ulm.de.
German Center for Child and Adolescent Health (DZKJ), Partner Site Ulm, Ulm, Germany. kerstin.felgentreff@uniklinik-ulm.de.

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