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

Autor:	Kozycki CT; 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., Kodati S; National Eye Institute, Bethesda, Maryland, USA., Huryn L; National Eye Institute, Bethesda, Maryland, USA., Wang H; Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA., Warner BM; National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA., Jani P; National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA., Hammoud D; Radiology and Imaging Sciences, National Institutes of Health Clinical Center, Bethesda, Maryland, USA., Abu-Asab MS; Section of Histopathology, National Eye Institute, Bethesda, Maryland, USA., Jittayasothorn Y; National Eye Institute, Bethesda, Maryland, USA., Mattapallil MJ; National Eye Institute, Bethesda, Maryland, USA., Tsai WL; National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA., Ullah E; Ophthalmic Genetics & Visual Function Branch, National Eye Institute, Bethesda, Maryland, USA., Zhou P; National Institute of Biological Sciences Beijing, Beijing, China., Tian X; National Institute of Biological Sciences Beijing, Beijing, China., Soldatos A; National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA., Moutsopoulos N; National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA., Kao-Hsieh M; National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA., Heller T; National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA., Cowen EW; Dermatology Branch, NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA., Lee CR; National Cancer Institute, Bethesda, Maryland, USA., Toro C; Undiagnosed Diseases Program, Bethesda, Maryland, USA.; National Human Genome Research Institute, Bethesda, Maryland, USA., Kalsi S; National Heart Lung and Blood Institute, Bethesda, Maryland, USA., Khavandgar Z; National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA., Baer A; National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA., Beach M; National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA., Long Priel D; Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA., Nehrebecky M; Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA., Rosenzweig S; Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA., Romeo T; Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA., Deuitch N; Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA.; Oncogenesis and Development Section, National Human Genome Research Institute, Bethesda, Maryland, USA., Brenchley L; National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA., Pelayo E; National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA., Zein W; National Eye Institute, Bethesda, Maryland, USA., Sen N; National Eye Institute, Bethesda, Maryland, USA., Yang AH; National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA., Farley G; Drs. Gilbert and Farley, OD, PC, Colonial Heights, Virginia, USA., Sweetser DA; Massachusetts General Hospital Center for Genomic Medicine, Boston, Massachusetts, USA.; Division of Medical Genetics & Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA., Briere L; Massachusetts General Hospital Center for Genomic Medicine, Boston, Massachusetts, USA., Yang J; Massachusetts Eye and Ear, Boston, Massachusetts, USA., de Oliveira Poswar F; Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.; Post Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil., Schwartz IVD; Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.; Post Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil., Silva Alves T; Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil., Dusser P; Service de Rhumatologie Pédiatrique, Centre de Référence des Maladies Auto-Inflammatoires de l'enfant, Hôpital Bicêtre, AP HP, Université Paris Sud, Bicetre, France., Koné-Paut I; Service de Rhumatologie Pédiatrique, Centre de Référence des Maladies Auto-Inflammatoires et de l'amylose inflammatoire CEREMAIA, Hôpital Bicêtre, AP HP, Université Paris Saclay, Bicetre, France., Touitou I; CeRéMAIA, CHU Montpellier, INSERM, University of Montpellier, Montpellier, France., Titah SM; Hôpital Fondation Adolphe de Rothschild, Paris, France., van Hagen PM; Depts Internal Medicine and Immunology, Erasmus MC, Rotterdam, The Netherlands., van Wijck RTA; Pathology & Clinical Bioinformatics, Erasmus MC, Rotterdam, The Netherlands., van der Spek PJ; Pathology & Clinical Bioinformatics, Erasmus MC, Rotterdam, The Netherlands., Yano H; Iizuka Hospital, Iizuka, Japan., Benneche A; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway., Apalset EM; Bergen Group of Epidemiology and Biomarkers in Rheumatic Disease, Department of Rheumatology, Haukeland University Hospital, Bergen, Norway., Jansson RW; Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway., Caspi RR; Laboratory of Immunology, National Eye Institute, NIH, Bethesda, Maryland, USA., Kuhns DB; Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA., Gadina M; National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA., Takada H; Department of Child Health, University of Tsukuba Faculty of Medicine, Tsukuba, Japan., Ida H; Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan., Nishikomori R; Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan., Verrecchia E; Department of Internal Medicine, Periodic Fevers Research Center, Università Cattolica del Sacro Cuore, Roma, Italy.; Dipartimento di scienze dell'invecchiamento, neurologiche, ortopediche e della testa-collo, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy., Sangiorgi E; Istitute of Genomic di Medicine, Universita Cattolica del Sacro Cuore, Roma, Italy., Manna R; Department of Internal Medicine, Periodic Fevers Research Center, Università Cattolica del Sacro Cuore, Roma, Italy., Brooks BP; Ophthalmic Genetics & Visual Function Branch, National Eye Institute, Bethesda, Maryland, USA., Sobrin L; Massachusetts Eye and Ear, Boston, Massachusetts, USA., Hufnagel RB; Ophthalmic Genetics & Visual Function Branch, National Eye Institute, Bethesda, Maryland, USA., Beck D; NYU, New York, New York, USA., Shao F; National Institute of Biological Sciences Beijing, Beijing, China., Ombrello AK; Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA., Aksentijevich I; Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA., Kastner DL; Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA christina.kozycki@nih.gov dan.kastner@nih.gov.
Jazyk:	angličtina
Zdroj:	Annals of the rheumatic diseases [Ann Rheum Dis] 2022 Oct; Vol. 81 (10), pp. 1453-1464. Date of Electronic Publication: 2022 Jul 22.
DOI:	10.1136/annrheumdis-2022-222629
Abstrakt:	Objectives: 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. Methods: 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. Results: 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-κB 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. Conclusion: ROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in ALPK1 and some features of disease are amenable to immunomodulatory therapy. Competing Interests: Competing interests: FS is a cofounder and stockholder of Pyrotech therapeutics, a company that aims to develop agonist/inhibitor drugs for ALPK1. RM has received honorary fees for lectures from SHIRE-TAKEDA- SANOFI- NOVARTIS-SOBI and Nida Sen is employed by Janssen. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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