Gain-of-function mutations inALPK1cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome
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Published:2022-07-22
Issue:10
Volume:81
Page:1453-1464
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ISSN:0003-4967
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Container-title:Annals of the Rheumatic Diseases
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language:en
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Short-container-title:Ann Rheum Dis
Author:
Kozycki Christina TorresORCID, Kodati Shilpa, Huryn Laryssa, Wang Hongying, Warner Blake MORCID, 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 Vanessa D, Silva Alves Tamires, Dusser Perrine, Koné-Paut IsabelleORCID, 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 Douglas Byron, Gadina Massimo, Takada Hidetoshi, Ida Hiroaki, Nishikomori Ryuta, Verrecchia Elena, Sangiorgi Eugenio, Manna Raffaele, Brooks Brian P, Sobrin Lucia, Hufnagel Robert B, Beck David, Shao Feng, Ombrello Amanda K, Aksentijevich Ivona, Kastner Daniel LORCID
Abstract
ObjectivesTo test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation inALPK1, is an autoinflammatory disease.MethodsThis cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect ofALPK1mutations 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 ofALPK1mutations on protein function and immune signalling.ResultsThe 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 theAlpk1T237M 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.ConclusionROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations inALPK1and some features of disease are amenable to immunomodulatory therapy.
Funder
National Human Genome Research Institute National Institute of Allergy and Infectious Diseases NIH Clinical Center The Hill Family Fund for the Diagnosis and Management of Rare and Undiagnosed Diseases at Mass General Hospital NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Direction National Eye Institute National Institute of Dental and Craniofacial Research
Subject
General Biochemistry, Genetics and Molecular Biology,Immunology,Immunology and Allergy,Rheumatology
Cited by
16 articles.
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