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 Lee; Camilo 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

doi:10.1136/annrheumdis-2022-222629

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

Research output: Contribution to journal › Article › peer-review

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. 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 language	English (US)
Pages (from-to)	1453-1464
Number of pages	12
Journal	Annals of the rheumatic diseases
Volume	81
Issue number	10
DOIs	https://doi.org/10.1136/annrheumdis-2022-222629
State	Published - Jul 22 2022
Externally published	Yes

Keywords

Amyloidosis
Arthritis
Immune System Diseases
Inflammation
Therapeutics

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
Rheumatology
Immunology and Allergy
Immunology

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10.1136/annrheumdis-2022-222629

Cite this

Kozycki, C. T., Kodati, S., Huryn, L., Wang, H., Warner, B. M., Jani, P., Hammoud, D., Abu-Asab, M. S., Jittayasothorn, Y., Mattapallil, M. J., Tsai, W. L., Ullah, E., Zhou, P., Tian, X., Soldatos, A., Moutsopoulos, N., Kao-Hsieh, M., Heller, T., Cowen, E. W., ... Kastner, D. L. (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. Annals of the rheumatic diseases, 81(10), 1453-1464. https://doi.org/10.1136/annrheumdis-2022-222629

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. / Kozycki, Christina Torres; Kodati, Shilpa; Huryn, Laryssa et al.
In: Annals of the rheumatic diseases, Vol. 81, No. 10, 22.07.2022, p. 1453-1464.

Research output: Contribution to journal › Article › peer-review

Kozycki, CT, Kodati, S, Huryn, L, Wang, H, Warner, BM, Jani, P, Hammoud, D, Abu-Asab, MS, Jittayasothorn, Y, Mattapallil, MJ, Tsai, WL, Ullah, E, Zhou, P, Tian, X, Soldatos, A, Moutsopoulos, N, Kao-Hsieh, M, Heller, T, Cowen, EW, Lee, CCR, Toro, C, Kalsi, S, Khavandgar, Z, Baer, A, Beach, M, Priel, DL, Nehrebecky, M, Rosenzweig, S, Romeo, T, Deuitch, N, Brenchley, L, Pelayo, E, Zein, W, Sen, N, Yang, AH, Farley, G, Sweetser, DA, Briere, L, Yang, J, De Oliveira Poswar, F, Schwartz, IVD, Alves, TS, Dusser, P, Koné-Paut, I, Touitou, I, Titah, SM, Van Hagen, PM, Van Wijck, RTA, Van Der Spek, PJ, Yano, H, Benneche, A, Apalset, EM, Jansson, RW, Caspi, RR, Kuhns, DB, Gadina, M, Takada, H, Ida, H, Nishikomori, R, Verrecchia, E, Sangiorgi, E, Manna, R, Brooks, BP, Sobrin, L, Hufnagel, RB, Beck, D, Shao, F, Ombrello, AK, Aksentijevich, I & Kastner, DL 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', Annals of the rheumatic diseases, vol. 81, no. 10, pp. 1453-1464. https://doi.org/10.1136/annrheumdis-2022-222629

@article{054ced9d3e6d482c9bcb31cb59fedadf,

title = "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",

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. 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.",

keywords = "Amyloidosis, Arthritis, Immune System Diseases, Inflammation, Therapeutics",

author = "Kozycki, {Christina Torres} and Shilpa Kodati and Laryssa Huryn and Hongying Wang and Warner, {Blake M.} and Priyam Jani and Dima Hammoud and Abu-Asab, {Mones S.} and Yingyos Jittayasothorn and Mattapallil, {Mary J.} and Tsai, {Wanxia Li} and Ehsan Ullah and Ping Zhou and Xiaoying Tian and Ariane Soldatos and Niki Moutsopoulos and Marie Kao-Hsieh and Theo Heller and Cowen, {Edward W.} and Lee, {Chyi Chia Richard} and Camilo Toro and Shelley Kalsi and Zohreh Khavandgar and Alan Baer and Margaret Beach and Priel, {Debra Long} and Michele Nehrebecky and Sofia Rosenzweig and Tina Romeo and Natalie Deuitch and Laurie Brenchley and Eileen Pelayo and Wadih Zein and Nida Sen and Yang, {Alexander H.} and Gary Farley and Sweetser, {David A.} and Lauren Briere and Janine Yang and {De Oliveira Poswar}, Fabiano and Schwartz, {Ida Vanessa D.} and Alves, {Tamires Silva} and Perrine Dusser and Isabelle Kon{\'e}-Paut and Isabelle Touitou and Titah, {Salah Mohamed} and {Van Hagen}, {Petrus Martin} and {Van Wijck}, {Rogier T.A.} and {Van Der Spek}, {Peter J.} and Hiromi Yano and Andreas Benneche and Apalset, {Ellen M.} and Jansson, {Ragnhild Wivestad} and Caspi, {Rachel R.} and Kuhns, {Douglas Byron} and Massimo Gadina and Hidetoshi Takada and Hiroaki Ida and Ryuta Nishikomori and Elena Verrecchia and Eugenio Sangiorgi and Raffaele Manna and Brooks, {Brian P.} and Lucia Sobrin and Hufnagel, {Robert B.} and David Beck and Feng Shao and Ombrello, {Amanda K.} and Ivona Aksentijevich and Kastner, {Daniel L.}",

note = "Publisher Copyright: {\textcopyright} ",

year = "2022",

month = jul,

day = "22",

doi = "10.1136/annrheumdis-2022-222629",

language = "English (US)",

volume = "81",

pages = "1453--1464",

journal = "Annals of the rheumatic diseases",

issn = "0003-4967",

publisher = "BMJ Publishing Group",

number = "10",

}

TY - JOUR

T1 - Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease

T2 - functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome

AU - Kozycki, Christina Torres

AU - Kodati, Shilpa

AU - Huryn, Laryssa

AU - Wang, Hongying

AU - Warner, Blake M.

AU - Jani, Priyam

AU - Hammoud, Dima

AU - Abu-Asab, Mones S.

AU - Jittayasothorn, Yingyos

AU - Mattapallil, Mary J.

AU - Tsai, Wanxia Li

AU - Ullah, Ehsan

AU - Zhou, Ping

AU - Tian, Xiaoying

AU - Soldatos, Ariane

AU - Moutsopoulos, Niki

AU - Kao-Hsieh, Marie

AU - Heller, Theo

AU - Cowen, Edward W.

AU - Lee, Chyi Chia Richard

AU - Toro, Camilo

AU - Kalsi, Shelley

AU - Khavandgar, Zohreh

AU - Baer, Alan

AU - Beach, Margaret

AU - Priel, Debra Long

AU - Nehrebecky, Michele

AU - Rosenzweig, Sofia

AU - Romeo, Tina

AU - Deuitch, Natalie

AU - Brenchley, Laurie

AU - Pelayo, Eileen

AU - Zein, Wadih

AU - Sen, Nida

AU - Yang, Alexander H.

AU - Farley, Gary

AU - Sweetser, David A.

AU - Briere, Lauren

AU - Yang, Janine

AU - De Oliveira Poswar, Fabiano

AU - Schwartz, Ida Vanessa D.

AU - Alves, Tamires Silva

AU - Dusser, Perrine

AU - Koné-Paut, Isabelle

AU - Touitou, Isabelle

AU - Titah, Salah Mohamed

AU - Van Hagen, Petrus Martin

AU - Van Wijck, Rogier T.A.

AU - Van Der Spek, Peter J.

AU - Yano, Hiromi

AU - Benneche, Andreas

AU - Apalset, Ellen M.

AU - Jansson, Ragnhild Wivestad

AU - Caspi, Rachel R.

AU - Kuhns, Douglas Byron

AU - Gadina, Massimo

AU - Takada, Hidetoshi

AU - Ida, Hiroaki

AU - Nishikomori, Ryuta

AU - Verrecchia, Elena

AU - Sangiorgi, Eugenio

AU - Manna, Raffaele

AU - Brooks, Brian P.

AU - Sobrin, Lucia

AU - Hufnagel, Robert B.

AU - Beck, David

AU - Shao, Feng

AU - Ombrello, Amanda K.

AU - Aksentijevich, Ivona

AU - Kastner, Daniel L.

PY - 2022/7/22

Y1 - 2022/7/22

N2 - 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.

AB - 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.

KW - Amyloidosis

KW - Arthritis

KW - Immune System Diseases

KW - Inflammation

KW - Therapeutics

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U2 - 10.1136/annrheumdis-2022-222629

DO - 10.1136/annrheumdis-2022-222629

M3 - Article

C2 - 35868845

AN - SCOPUS:85135759296

SN - 0003-4967

VL - 81

SP - 1453

EP - 1464

JO - Annals of the rheumatic diseases

JF - Annals of the rheumatic diseases

IS - 10

ER -

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

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