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 - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Annals of the Rheumatic Diseases Année : 2022

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

Shilpa Kodati
  • Fonction : Auteur
Laryssa Huryn
  • Fonction : Auteur
Blake Warner
Priyam Jani
  • Fonction : Auteur
Mones Abu-Asab
  • Fonction : Auteur
Yingyos Jittayasothorn
  • Fonction : Auteur
Mary Mattapallil
  • Fonction : Auteur
Wanxia Li Tsai
  • Fonction : Auteur
Ehsan Ullah
  • Fonction : Auteur
Ping Zhou
  • Fonction : Auteur
Xiaoying Tian
  • Fonction : Auteur
Niki Moutsopoulos
  • Fonction : Auteur
Marie Kao-Hsieh
  • Fonction : Auteur
Edward Cowen
  • Fonction : Auteur
Zohreh Khavandgar
  • Fonction : Auteur
Alan Baer
  • Fonction : Auteur
Margaret Beach
  • Fonction : Auteur
Laurie Brenchley
  • Fonction : Auteur
Eileen Pelayo
  • Fonction : Auteur
Wadih Zein
  • Fonction : Auteur
Nida Sen
  • Fonction : Auteur
Gary Farley
  • Fonction : Auteur
Janine Yang
  • Fonction : Auteur
Hiromi Yano
  • Fonction : Auteur
Rachel Caspi
  • Fonction : Auteur
Massimo Gadina
  • Fonction : Auteur
Brian Brooks
  • Fonction : Auteur
Lucia Sobrin
  • Fonction : Auteur
Robert Hufnagel
  • Fonction : Auteur
Feng Shao
  • Fonction : Auteur

Résumé

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.
Fichier principal
Vignette du fichier
1453.full.pdf (5.8 Mo) Télécharger le fichier
Origine Fichiers éditeurs autorisés sur une archive ouverte
Licence

Dates et versions

hal-04438180 , version 1 (05-02-2024)

Licence

Identifiants

Citer

Christina Torres Kozycki, Shilpa Kodati, Laryssa Huryn, Hongying Wang, Blake Warner, et al.. 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. Annals of the Rheumatic Diseases, 2022, 81 (10), pp.1453-1464. ⟨10.1136/annrheumdis-2022-222629⟩. ⟨hal-04438180⟩
9 Consultations
3 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More