Dominant negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes

Bergithe E. Oftedal; Kristian Assing; Safa Baris; Stephanie L. Safgren; Isik S. Johansen; Marianne Antonius Jakobsen; Dusica Babovic-Vuksanovic; Katherine Agre; Eric W. Klee; Emina Majcic; Elise M.N. Ferré; Monica M. Schmitt; Tom DiMaggio; Lindsey B. Rosen; Muhammad Obaidur Rahman; Dionisios Chrysis; Aristeidis Giannakopoulos; Maria Tallon Garcia; Luis Ignacio González-Granado; Katherine Stanley; Jessica Galant-Swafford; Pim Suwannarat; Isabelle Meyts; Michail S. Lionakis; Eystein S. Husebye

doi:10.1016/j.isci.2023.106818

Dominant negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes

Bergithe E. Oftedal^*, Kristian Assing, Safa Baris, Stephanie L. Safgren, Isik S. Johansen, Marianne Antonius Jakobsen, Dusica Babovic-Vuksanovic, Katherine Agre, Eric W. Klee, Emina Majcic, Elise M.N. Ferré, Monica M. Schmitt, Tom DiMaggio, Lindsey B. Rosen, Muhammad Obaidur Rahman, Dionisios Chrysis, Aristeidis Giannakopoulos, Maria Tallon Garcia, Luis Ignacio González-Granado, Katherine StanleyJessica Galant-Swafford, Pim Suwannarat, Isabelle Meyts, Michail S. Lionakis, Eystein S. Husebye^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disease characterized by severe and childhood onset organ-specific autoimmunity caused by mutations in the autoimmune regulator (AIRE) gene. More recently, dominant-negative mutations within the PHD1, PHD2, and SAND domains have been associated with an incompletely penetrant milder phenotype with later onset familial clustering, often masquerading as organ-specific autoimmunity. Patients with immunodeficiencies or autoimmunity where genetic analyses revealed heterozygous AIRE mutations were included in the study and the dominant-negative effects of the AIRE mutations were functionally assessed in vitro. We here report additional families with phenotypes ranging from immunodeficiency, enteropathy, and vitiligo to asymptomatic carrier status. APS-1-specific autoantibodies can hint to the presence of these pathogenic AIRE variants although their absence does not rule out their presence. Our findings suggest functional studies of heterozygous AIRE variants and close follow-up of identified individuals and their families.

Original language	English
Article number	106818
Journal	iScience
Volume	26
Issue number	6
Number of pages	17
ISSN	2589-0042
DOIs	https://doi.org/10.1016/j.isci.2023.106818
Publication status	Published - 16. Jun 2023

Keywords

Human Genetics
Molecular genetics

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10.1016/j.isci.2023.106818Licence: CC BY

Open Access VersionFinal published version, 3.35 MBLicence: CC BY

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Oftedal, B. E., Assing, K., Baris, S., Safgren, S. L., Johansen, I. S., Jakobsen, M. A., Babovic-Vuksanovic, D., Agre, K., Klee, E. W., Majcic, E., Ferré, E. M. N., Schmitt, M. M., DiMaggio, T., Rosen, L. B., Rahman, M. O., Chrysis, D., Giannakopoulos, A., Garcia, M. T., González-Granado, L. I., ... Husebye, E. S. (2023). Dominant negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes. iScience, 26(6), Article 106818. https://doi.org/10.1016/j.isci.2023.106818

@article{e3283ce8836949018f6bf73071f0a440,

title = "Dominant negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes",

abstract = "Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disease characterized by severe and childhood onset organ-specific autoimmunity caused by mutations in the autoimmune regulator (AIRE) gene. More recently, dominant-negative mutations within the PHD1, PHD2, and SAND domains have been associated with an incompletely penetrant milder phenotype with later onset familial clustering, often masquerading as organ-specific autoimmunity. Patients with immunodeficiencies or autoimmunity where genetic analyses revealed heterozygous AIRE mutations were included in the study and the dominant-negative effects of the AIRE mutations were functionally assessed in vitro. We here report additional families with phenotypes ranging from immunodeficiency, enteropathy, and vitiligo to asymptomatic carrier status. APS-1-specific autoantibodies can hint to the presence of these pathogenic AIRE variants although their absence does not rule out their presence. Our findings suggest functional studies of heterozygous AIRE variants and close follow-up of identified individuals and their families.",

keywords = "Human Genetics, Molecular genetics",

author = "Oftedal, {Bergithe E.} and Kristian Assing and Safa Baris and Safgren, {Stephanie L.} and Johansen, {Isik S.} and Jakobsen, {Marianne Antonius} and Dusica Babovic-Vuksanovic and Katherine Agre and Klee, {Eric W.} and Emina Majcic and Ferr{\'e}, {Elise M.N.} and Schmitt, {Monica M.} and Tom DiMaggio and Rosen, {Lindsey B.} and Rahman, {Muhammad Obaidur} and Dionisios Chrysis and Aristeidis Giannakopoulos and Garcia, {Maria Tallon} and Gonz{\'a}lez-Granado, {Luis Ignacio} and Katherine Stanley and Jessica Galant-Swafford and Pim Suwannarat and Isabelle Meyts and Lionakis, {Michail S.} and Husebye, {Eystein S.}",

note = "https://doi.org/10.1016/j.isci.2023.106818",

year = "2023",

month = jun,

day = "16",

doi = "10.1016/j.isci.2023.106818",

language = "English",

volume = "26",

journal = "iScience",

issn = "2589-0042",

publisher = "Elsevier",

number = "6",

}

Oftedal, BE, Assing, K, Baris, S, Safgren, SL, Johansen, IS, Jakobsen, MA, Babovic-Vuksanovic, D, Agre, K, Klee, EW, Majcic, E, Ferré, EMN, Schmitt, MM, DiMaggio, T, Rosen, LB, Rahman, MO, Chrysis, D, Giannakopoulos, A, Garcia, MT, González-Granado, LI, Stanley, K, Galant-Swafford, J, Suwannarat, P, Meyts, I, Lionakis, MS & Husebye, ES 2023, 'Dominant negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes', iScience, vol. 26, no. 6, 106818. https://doi.org/10.1016/j.isci.2023.106818

TY - JOUR

T1 - Dominant negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes

AU - Oftedal, Bergithe E.

AU - Assing, Kristian

AU - Baris, Safa

AU - Safgren, Stephanie L.

AU - Johansen, Isik S.

AU - Jakobsen, Marianne Antonius

AU - Babovic-Vuksanovic, Dusica

AU - Agre, Katherine

AU - Klee, Eric W.

AU - Majcic, Emina

AU - Ferré, Elise M.N.

AU - Schmitt, Monica M.

AU - DiMaggio, Tom

AU - Rosen, Lindsey B.

AU - Rahman, Muhammad Obaidur

AU - Chrysis, Dionisios

AU - Giannakopoulos, Aristeidis

AU - Garcia, Maria Tallon

AU - González-Granado, Luis Ignacio

AU - Stanley, Katherine

AU - Galant-Swafford, Jessica

AU - Suwannarat, Pim

AU - Meyts, Isabelle

AU - Lionakis, Michail S.

AU - Husebye, Eystein S.

N1 - https://doi.org/10.1016/j.isci.2023.106818

PY - 2023/6/16

Y1 - 2023/6/16

N2 - Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disease characterized by severe and childhood onset organ-specific autoimmunity caused by mutations in the autoimmune regulator (AIRE) gene. More recently, dominant-negative mutations within the PHD1, PHD2, and SAND domains have been associated with an incompletely penetrant milder phenotype with later onset familial clustering, often masquerading as organ-specific autoimmunity. Patients with immunodeficiencies or autoimmunity where genetic analyses revealed heterozygous AIRE mutations were included in the study and the dominant-negative effects of the AIRE mutations were functionally assessed in vitro. We here report additional families with phenotypes ranging from immunodeficiency, enteropathy, and vitiligo to asymptomatic carrier status. APS-1-specific autoantibodies can hint to the presence of these pathogenic AIRE variants although their absence does not rule out their presence. Our findings suggest functional studies of heterozygous AIRE variants and close follow-up of identified individuals and their families.

AB - Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disease characterized by severe and childhood onset organ-specific autoimmunity caused by mutations in the autoimmune regulator (AIRE) gene. More recently, dominant-negative mutations within the PHD1, PHD2, and SAND domains have been associated with an incompletely penetrant milder phenotype with later onset familial clustering, often masquerading as organ-specific autoimmunity. Patients with immunodeficiencies or autoimmunity where genetic analyses revealed heterozygous AIRE mutations were included in the study and the dominant-negative effects of the AIRE mutations were functionally assessed in vitro. We here report additional families with phenotypes ranging from immunodeficiency, enteropathy, and vitiligo to asymptomatic carrier status. APS-1-specific autoantibodies can hint to the presence of these pathogenic AIRE variants although their absence does not rule out their presence. Our findings suggest functional studies of heterozygous AIRE variants and close follow-up of identified individuals and their families.

KW - Human Genetics

KW - Molecular genetics

U2 - 10.1016/j.isci.2023.106818

DO - 10.1016/j.isci.2023.106818

M3 - Journal article

C2 - 37235056

SN - 2589-0042

VL - 26

JO - iScience

JF - iScience

IS - 6

M1 - 106818

ER -

Dominant negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes

Abstract

Keywords

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