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Non-Skewed X-inactivation Results in NF-κB Essential Modulator (NEMO) Δ-exon 5-autoinflammatory Syndrome (NEMO-NDAS) in a Female with Incontinentia Pigmenti.
Eigemann, Jessica; Janda, Ales; Schuetz, Catharina; Lee-Kirsch, Min Ae; Schulz, Ansgar; Hoenig, Manfred; Furlan, Ingrid; Jacobsen, Eva-Maria; Zinngrebe, Julia; Peters, Sarah; Drewes, Cosima; Siebert, Reiner; Rump, Eva-Maria; Führer, Marita; Lorenz, Myriam; Pannicke, Ulrich; Kölsch, Uwe; Debatin, Klaus-Michael; von Bernuth, Horst; Schwarz, Klaus; Felgentreff, Kerstin.
Afiliação
  • Eigemann J; Master's Program of Molecular Medicine, Medical Faculty of Ulm University, Ulm, Germany.
  • Janda A; Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
  • Schuetz C; Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
  • Lee-Kirsch MA; Department of Pediatrics, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • Schulz A; German Center for Child and Adolescent Health (DZKJ), Partner Site Leipzig/Dresden, Dresden, Germany.
  • Hoenig M; Department of Pediatrics, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • Furlan I; German Center for Child and Adolescent Health (DZKJ), Partner Site Leipzig/Dresden, Dresden, Germany.
  • Jacobsen EM; Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
  • Zinngrebe J; German Center for Child and Adolescent Health (DZKJ), Partner Site Ulm, Ulm, Germany.
  • Peters S; Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
  • Drewes C; German Center for Child and Adolescent Health (DZKJ), Partner Site Ulm, Ulm, Germany.
  • Siebert R; Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
  • Rump EM; Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
  • Führer M; Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
  • Lorenz M; Department of Clinical Chemistry, Ulm University Medical Center, Ulm, Germany.
  • Pannicke U; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.
  • Kölsch U; German Center for Child and Adolescent Health (DZKJ), Partner Site Ulm, Ulm, Germany.
  • Debatin KM; Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.
  • von Bernuth H; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg - Hessen, Ulm, Germany.
  • Schwarz K; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg - Hessen, Ulm, Germany.
  • Felgentreff K; Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
J Clin Immunol ; 45(1): 1, 2024 Sep 12.
Article em En | MEDLINE | ID: mdl-39264518
ABSTRACT

PURPOSE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Incontinência Pigmentar / Éxons / Quinase I-kappa B / Inativação do Cromossomo X Limite: Adult / Female / Humans Idioma: En Revista: J Clin Immunol Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Holanda
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Incontinência Pigmentar / Éxons / Quinase I-kappa B / Inativação do Cromossomo X Limite: Adult / Female / Humans Idioma: En Revista: J Clin Immunol Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Holanda