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A Proactive Missense Variant Atlas for the Autoimmune Regulator

Award Number: R21AI173827
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/13/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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A Proactive Missense Variant Atlas for the Autoimmune Regulator - Project Summary/Abstract Pathogenic variants of the Autoimmune Regulator (AIRE) gene cause the primary immunodeficiency disease Autoimmune Polyendocrine Syndrome Type 1 (APS-1; also called Autoimmune Polyendocrinopathy with Candidiasis and Ectodermal Dystrophy), which manifests as symptoms including chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease among other autoimmune symptoms. AIRE prevents autoimmunity by increasing the expression of tissue-specific genes in the niche of developing T cells, allowing for the elimination of emerging self-reactive T-cells before they can mature. Sequencing of AIRE is an increasingly common tool to diagnose APS-1, and earlier diagnosis can benefit patients. However, diagnosis is limited by the fact that two thirds of variants are missense, and that more than half of the missense variants found are “of unknown significance”. Testing the function of variants in cultured cells can provide strong evidence for more informative variant classification, but these tests are carried out reactively, often months or years after a new variant is first observed in a patient. A proactive solution to this problem is to efficiently assess the function of all possible missense variants to generate a sequence-function map. Such maps can provide immediate and accurate evidence to diagnose disease, even for never-before-seen variants. We have developed and validated one scalable assay for testing AIRE missense variants, using human cells with a fluorescent reporter of insulin promoter activity, and are exploring other scalable assays. We will: 1) Generate a sequence-function map to enable more accurate clinical interpretation of AIRE missense variants and; 2) Validate and characterize the AIRE sequence-function map. A sequence-function map of AIRE will provide key proactive evidence for rapid and definitive genetic diagnosis of APS-1, and ultimately more positive patient outcomes.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$829 )
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	002	2	4/29/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$829
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	2	12/11/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$77,197
2025	2023	THE GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON			CAN	Allergy and Infectious Diseases Research	000	1	12/11/2024	NEW	-$77,197
														Subtotal = -$829

Issue Date FY: 2024 ( Subtotal = $238,500 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	2	3/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$214,650
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	002	2	4/16/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$23,850
2024	2023	THE GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON			CAN	Allergy and Infectious Diseases Research	000	1	3/5/2024	NEW	$0
														Subtotal = $238,500

Issue Date FY: 2023 ( Subtotal = $135,000 )
2023	2023	GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON			CAN	Allergy and Infectious Diseases Research	000	1	2/13/2023	NEW	$135,000
														Subtotal = $135,000

Grand Total All Awards = $372,671

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A Proactive Missense Variant Atlas for the Autoimmune Regulator

Award Number: R21AI173827

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/13/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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