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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)1453-1464
Number of pages12
JournalAnnals of the Rheumatic Diseases
Issue number10
Publication statusPublished - 12 Sept 2022

Bibliographical note

Funding Information:
This work was supported by the Divisions of Intramural Research of the National Human Genome Research Institute, the National Institute of Allergy and Infectious Diseases, the National Eye Institute, and the National Institute for Dental and Craniofacial Research, as well as the NIH Clinical Centre, the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Direction (U01HG007690 (DAS, LCB)) and the Hill Family Fund for the Diagnosis and Management of Rare and Undiagnosed Diseases at Mass General Hospital.

© Author(s) (or their employer(s)) 2022.


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