biostudies-literatureKozycki CTNational Institute of Allergy and Infectious DiseasesIntramural NIH HHSNational Eye InstituteNIH Common Fund, through the Office of Strategic Coordination/Office of the NIH DirectionThe Hill Family Fund for the Diagnosis and Management of Rare and Undiagnosed Diseases at Mass General HospitalNHGRI NIH HHSNIH Clinical CenterNational Institute of Dental and Craniofacial ResearchNational Human Genome Research Institute1453-1464https://www.ebi.ac.uk/biostudies/studies/S-EPMC9484401biostudies-literatureUnknown81(10)<h4>Objectives</h4>To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in <i>ALPK1</i>, is an autoinflammatory disease.<h4>Methods</h4>This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of <i>ALPK1</i> 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 <i>ALPK1</i> mutations on protein function and immune signalling.<h4>Annals of the rheumatic diseasesGain-of-function mutations in &lt;i&gt;ALPK1&lt;/i&gt; cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome.PMC9484401U01 HG007690Z01 DE000704Z01-DE000704U01 HG007703EY000477U01HG007690Dasari SUndiagnosed Diseases NetworkNishikomori RLiu XZYang AHEmrick LTPelayo EJansson RWSolem EGutierrez INovacic DMalicdan MCVNehrebecky MWorley KSutton SDon Hadley SHCunningham MTitah SMSilva Alves TAmendola LButte MJJobanputra VWalker MStoler JMDusser PJean-Marie OLawrence Merritt JBennet JWarner BMBonner DMoretti PMWeisz-Hubshman MCooper CMLoo SKSmith ECCoakley TRAbu-Asab MSPalmer CGFieg ELPapp JCAcosta MTSessions Cole FPosey JELanza IRSilverman EKBaer ASchwartz IVDLee CRForghani IManna RDayal JGJarvik GPSobrin LVogel TPAdams DRDeardorff MDuncan LKrakow DZhao CByers PMartin MGAzamian MSCowen EWApalset EMBale JFisher PGFogel BLRenteria GMahoney RSinsheimer JSLanpher BCIzumi KScott DAMcCray ATTian XWhitlock JNewman JHUllah EChang TPSweetser DAHuryn LOmbrello AKKoziura MAdam MAlvey JTran AAGochuico BMacnamara EFCarrasquillo OCobban LANickerson DBerg-Rood BPusey BNRaper ADavis JMarth GCogan JDSchaechter JWang LKKalsi SNicholas SKBivona STabor HKBejerano GJarvik JCraigen WJMight MBriere LBoyd BKennedy JIsasi Rde Oliveira Poswar FZein WTucker BMWangler MFKuhns DBKaraviti LPak SZuchner SWenger MWBayrak-Toydemir PHisama FMMartin BAMoutsopoulos NHayes NLongo NKetkar SRosenfeld JAJamal FMao RFarley GLiu PSullivan KMamounas LAWallace SWambach JKone-Paut IEsteban CLalani SRJani PDorrani NParker NHBlue ESaporta MOrengo JPThorson WHammoud DTelischi FWheeler MTHing AHorike-Pyne MHeller TMartinez-Agosto JAMattapallil MJKilich GCaspi RRBamshad MZhang ZBrooks BPTekin MEng CMD'Souza PHom JKravets ECarl Pallais JBenneche ADeuitch NNelson SFSmith KSLaMoure GLSybert VKodati SIntrone WKrasnewich DMBohnsack JUrv TKAngelica DTifft CJWan JLong Priel DBaldridge DLewis RAKhavandgar ZIda HAksentijevich IHolm IASacco RKastner DLSolnica-Krezel LClark GDLeeRoyLevitt BHKozycki CTHufnagel RBMak BCMcCauley JSoldatos ARodan LHByrd WEKohane ISNieves-Rodriguez SBeck APerry KWBeck DPotocki LGrajewski ACrouse ABGlass IWegner DDoss ALRon Scott Cvan Hagen PMVerrecchia EShao FRives LCoggins MSangiorgi EAndrews AKiley DKohler JNShashi VBehrens ETan ALMBotto LAshley EABacino CAChanprasert SRomeo TEckstein DJBarbouth DBriere LCFernandez LQuinlan AZhou PRuzhnikov MMaravilla KBeggs AHMarwaha SNakano-Okuno MHuang YHamid RZastrow DBReuter CMBellen HXiao Cvan Wijck RTADai HRaja ANSisco KRosenzweig SSun AVanderver ABalasubramanyam ABurrage LCShin JBeach MBrown GSchoch KWang HMarom RKao-Hsieh MManolio TAToro CJittayasothorn YPace LGoldrich MPCassini TChao HTEsteves CHuang AOglesbee DYang JVelinder MMcConkie-Rosell AMorava EMaduro VVYamamoto SSen NViskochil DCarey JTakada HSampson JBBademci GYano HFalk MBen Solomon RCSHigh FBernstein JABerry GTBrenchley LTsai WLBican ABurke EABrokamp EKobren SNLam BLeBlanc KLam CRossignol FWalley NMRobertson AKHassey KCope HWard PAGadina MEarl DMcGee EMacRae CAMefford HSullivan JADoherty DMirzaa GPhillipsIII JARosenwasser NMaas RLTouitou IColley HAGahl WALoscalzo JSchedl TJayadev SRao DAvan der Spek PJDipple KWolfe LAKorrick SRaskind WGodfrey RATan QKWesterfield MDouine EDWahl CEGolden-Grant KfalseGain-of-function mutations in &lt;i&gt;ALPK1&lt;/i&gt; cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome.<h4>Objectives</h4>To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in <i>ALPK1</i>, is an autoinflammatory disease.<h4>Methods</h4>This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of <i>ALPK1</i> 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 <i>ALPK1</i> mutations on protein function and immune signalling.<h4>2022-01-01T00:00:00Z2022 Oct2026-07-14T17:53:44.235Z2024-11-06T07:09:15.197ZS-EPMC94844013586884510.1136/annrheumdis-2022-222629