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 A. Huryn, Hongying Wang, Blake M. Warner, Priyam Jani, Dima A. Hammoud, Mones Abu‐Asab, Yingyos Jittayasothorn, Mary J. Mattapallil, Wanxia Li Tsai, Ehsan Ullah, Ping‐Kun Zhou, Xiaoying Tian, Ariane Soldatos, Niki M. Moutsopoulos, Marie Kao-Hsieh, Theo Heller, Edward W. Cowen, Chyi‐Chia Richard Lee, Camilo Toro, Shelley S. Kalsi, Zohreh Khavandgar, Alan N. Baer, Margaret Beach, Debra Long Priel, Michele Nehrebecky, Sofia Rosenzweig, Tina Romeo, Natalie Deuitch, Laurie Brenchley, Eileen Pelayo, Wadih M. Zein, Nida Sen, Alexander H. Yang, Gary L. Farley, David A. Sweetser, Lauren C. Briere, Janine Yang, Fabiano de Oliveira Poswar, Ida Vanessa Döederlein Schwartz, Tamires Silva Alves, Perrine Dusser, Isabelle Koné‐Paut, Isabelle Touitou, Salah Mohamed Titah, P. 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 B. Kuhns, Massimo Gadina, Hidetoshi Takada, Hiroaki Ida, Ryuta Nishikomori, Elena Verrecchia, Eugenio Sangiorgi, Raffaele Manna, Brian P. Brooks, Lucia Sobrin, Robert B. Hufnagel, David B. Beck, Feng Shao, Amanda K. Ombrello, Ivona Aksentijevich, Daniel L. Kastner, Maria T. Acosta, Margaret Adam, David R. Adams, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Devon Bonner, Lorenzo Botto
Abstract
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.