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Gain-of-function mutations in ALPK1 cause an NF-?B-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome

  1. Author:
    Kozycki, Christina Torres [ORCID]
    Kodati, Shilpa
    Huryn, Laryssa
    Wang, Hongying
    Warner, Blake M [ORCID]
    Jani, Priyam
    Hammoud, Dima
    Abu-Asab, Mones S
    Jittayasothorn, Yingyos
    Mattapallil, Mary J
    Tsai, Wanxia Li
    Ullah, Ehsan
    Zhou, Ping
    Tian, Xiaoying
    Soldatos, Ariane
    Moutsopoulos, Niki
    Kao-Hsieh, Marie
    Heller, Theo
    Cowen, Edward W
    Lee, Chyi-Chia Richard
    Toro, Camilo
    Kalsi, Shelley
    Khavandgar, Zohreh
    Baer, Alan
    Beach, Margaret
    Long-Priel,Debra
    Nehrebecky, Michele
    Rosenzweig, Sofia
    Romeo, Tina
    Deuitch, Natalie
    Brenchley, Laurie
    Pelayo, Eileen
    Zein, Wadih
    Sen, Nida
    Yang, Alexander H
    Farley, Gary
    Sweetser, David A
    Briere, Lauren
    Yang, Janine
    de Oliveira Poswar, Fabiano
    Schwartz, Ida
    Silva Alves, Tamires
    Dusser, Perrine
    Koné-Paut, Isabelle [ORCID]
    Touitou, Isabelle
    Titah, Salah Mohamed
    van Hagen, Petrus Martin
    van Wijck, Rogier T A
    van der Spek, Peter J
    Yano, Hiromi
    Benneche, Andreas
    Apalset, Ellen M
    Jansson, Ragnhild Wivestad
    Caspi, Rachel R
    Kuhns,Doug
    Gadina, Massimo
    Takada, Hidetoshi
    Ida, Hiroaki
    Nishikomori, Ryuta
    Verrecchia, Elena
    Sangiorgi, Eugenio
    Manna, Raffaele
    Brooks, Brian P
    Sobrin, Lucia
    Hufnagel, Robert
    Beck, David
    Shao, Feng
    Ombrello, Amanda K
    Aksentijevich, Ivona
    Kastner, Daniel L [ORCID]

  2. Author Address

    Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA christina.kozycki@nih.gov dan.kastner@nih.gov., National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA., National Eye Institute, Bethesda, Maryland, USA., Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA., National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA., Radiology and Imaging Sciences, National Institutes of Health Clinical Center, Bethesda, Maryland, USA., Section of Histopathology, National Eye Institute, Bethesda, Maryland, USA., National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA., Ophthalmic Genetics & Visual Function Branch, National Eye Institute, Bethesda, Maryland, USA., National Institute of Biological Sciences Beijing, Beijing, China., National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA., Dermatology Branch, NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA., National Cancer Institute, Bethesda, Maryland, USA., Undiagnosed Diseases Program, Bethesda, Maryland, USA., National Heart Lung and Blood Institute, Bethesda, Maryland, USA., Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA., Oncogenesis and Development Section, National Human Genome Research Institute, Bethesda, Maryland, USA., Drs. Gilbert and Farley, OD, PC, Colonial Heights, Virginia, USA., Massachusetts General Hospital Center for Genomic Medicine, Boston, Massachusetts, USA., Division of Medical Genetics & Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA., Massachusetts Eye and Ear, Boston, Massachusetts, USA., Hospital de Cl 237;nicas de Porto Alegre, Porto Alegre, Brazil., Post Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil., Service de Rhumatologie P 233;diatrique, Centre de R 233;f 233;rence des Maladies Auto-Inflammatoires de l 39;enfant, H 244;pital Bic 234;tre, AP HP, Universit 233; Paris Sud, Bicetre, France., Service de Rhumatologie P 233;diatrique, Centre de R 233;f 233;rence des Maladies Auto-Inflammatoires et de l 39;amylose inflammatoire CEREMAIA, H 244;pital Bic 234;tre, AP HP, Universit 233; Paris Saclay, Bicetre, France., CeR 233;MAIA, CHU Montpellier, INSERM, University of Montpellier, Montpellier, France., H 244;pital Fondation Adolphe de Rothschild, Paris, France., Depts Internal Medicine and Immunology, Erasmus MC, Rotterdam, The Netherlands., Pathology & Clinical Bioinformatics, Erasmus MC, Rotterdam, The Netherlands., Iizuka Hospital, Iizuka, Japan., Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway., Bergen Group of Epidemiology and Biomarkers in Rheumatic Disease, Department of Rheumatology, Haukeland University Hospital, Bergen, Norway., Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway., Laboratory of Immunology, National Eye Institute, NIH, Bethesda, Maryland, USA., Department of Child Health, University of Tsukuba Faculty of Medicine, Tsukuba, Japan., Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan., Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan., Department of Internal Medicine, Periodic Fevers Research Center, Universit 224; Cattolica del Sacro Cuore, Roma, Italy., Dipartimento di scienze dell 39;invecchiamento, neurologiche, ortopediche e della testa-collo, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy., Istitute of Genomic di Medicine, Universita Cattolica del Sacro Cuore, Roma, Italy., NYU, New York, New York, USA.,
    1. Year: 2022
    2. Date: Jul 22
    3. Epub Date: 2022 07 22
  2. Journal: Annals of the Rheumatic Diseases
  4. Type of Article: Article
  1. Abstract:

    To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in ALPK1, is an autoinflammatory disease. This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of ALPK1 mutations on immune signalling. Clinical, immunologic and radiographical examinations were performed, and 10 patients were empirically initiated on anticytokine therapy and monitored. Exome sequencing was used to identify a new pathogenic variant. Cytokine profiling, transcriptomics, immunoblotting and knock-in mice were used to assess the impact of ALPK1 mutations on protein function and immune signalling. The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys.Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients).Patients' primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-?B signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation.Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow. ROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in ALPK1 and some features of disease are amenable to immunomodulatory therapy. © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

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  2. DOI: 10.1136/annrheumdis-2022-222629
  3. PMID: 35868845
  4. PII : annrheumdis-2022-222629

Library Notes

  1. Fiscal Year: FY2021-2022
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