The activating p.Ser466Arg change in STAT1 causes a peculiar phenotype with features of interferonopathies

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Abstract

Signal Transducer and Activator of Transcription 1 (STAT1) is a DNA-binding signal transducer that regulates transcription of specific genes in response to IFNγ and IFNα/β stimulation. Loss-of-function mutations impairing STAT1 activity are known to confer susceptibility to intracellular bacterial and viral diseases. Conversely, the few known activating mutations of STAT1 allow predisposition to chronic mucocutaneous candidiasis disease, and occur in patients with combined immunodeficiency and defective Th1 and Th17 responses. Here, we report on a de novo gain-of-function (GoF) STAT1 mutation (c.1398C>G, p.Ser466Arg) identified by exome sequencing in an individual with brain calcification, arthritis, recurrent pericarditis, leukopenia, thrombocytopenia and low C3 levels, a phenotype resembling an interferonopathy. The Ser466Arg change affects a highly conserved residue located in the DNA binding domain of the protein and the amino acid substitution was documented to have an activating role both in vitro and in vivo. Altogether, clinical features and functional studies are compatible with hyperactivation of the Interferon pathways, highlighting a role of STAT1 GoF mutation in clinical phenotypes fitting interferonopathies.

Original languageEnglish
JournalClinical Genetics
DOIs
Publication statusE-pub ahead of print - Aug 25 2019

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STAT1 Transcription Factor
Phenotype
Mutation
Chronic Mucocutaneous Candidiasis
Exome
Pericarditis
Leukopenia
DNA-Binding Proteins
Virus Diseases
Amino Acid Substitution
Transducers
Thrombocytopenia
Interferons
Arthritis
DNA
Brain
Genes

Cite this

@article{86edf02e8a584230b3ad5ac6765cd673,
title = "The activating p.Ser466Arg change in STAT1 causes a peculiar phenotype with features of interferonopathies",
abstract = "Signal Transducer and Activator of Transcription 1 (STAT1) is a DNA-binding signal transducer that regulates transcription of specific genes in response to IFNγ and IFNα/β stimulation. Loss-of-function mutations impairing STAT1 activity are known to confer susceptibility to intracellular bacterial and viral diseases. Conversely, the few known activating mutations of STAT1 allow predisposition to chronic mucocutaneous candidiasis disease, and occur in patients with combined immunodeficiency and defective Th1 and Th17 responses. Here, we report on a de novo gain-of-function (GoF) STAT1 mutation (c.1398C>G, p.Ser466Arg) identified by exome sequencing in an individual with brain calcification, arthritis, recurrent pericarditis, leukopenia, thrombocytopenia and low C3 levels, a phenotype resembling an interferonopathy. The Ser466Arg change affects a highly conserved residue located in the DNA binding domain of the protein and the amino acid substitution was documented to have an activating role both in vitro and in vivo. Altogether, clinical features and functional studies are compatible with hyperactivation of the Interferon pathways, highlighting a role of STAT1 GoF mutation in clinical phenotypes fitting interferonopathies.",
author = "Emilia Stellacci and Moneta, {Gian M} and Alessandro Bruselles and Sabina Barresi and Simone Pizzi and Giuliano Torre and {De Benedetti}, Fabrizio and Marco Tartaglia and Antonella Insalaco",
note = "{\circledC} 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.",
year = "2019",
month = "8",
day = "25",
doi = "10.1111/cge.13632",
language = "English",
journal = "Clinical Genetics",
issn = "0009-9163",
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TY - JOUR

T1 - The activating p.Ser466Arg change in STAT1 causes a peculiar phenotype with features of interferonopathies

AU - Stellacci, Emilia

AU - Moneta, Gian M

AU - Bruselles, Alessandro

AU - Barresi, Sabina

AU - Pizzi, Simone

AU - Torre, Giuliano

AU - De Benedetti, Fabrizio

AU - Tartaglia, Marco

AU - Insalaco, Antonella

N1 - © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

PY - 2019/8/25

Y1 - 2019/8/25

N2 - Signal Transducer and Activator of Transcription 1 (STAT1) is a DNA-binding signal transducer that regulates transcription of specific genes in response to IFNγ and IFNα/β stimulation. Loss-of-function mutations impairing STAT1 activity are known to confer susceptibility to intracellular bacterial and viral diseases. Conversely, the few known activating mutations of STAT1 allow predisposition to chronic mucocutaneous candidiasis disease, and occur in patients with combined immunodeficiency and defective Th1 and Th17 responses. Here, we report on a de novo gain-of-function (GoF) STAT1 mutation (c.1398C>G, p.Ser466Arg) identified by exome sequencing in an individual with brain calcification, arthritis, recurrent pericarditis, leukopenia, thrombocytopenia and low C3 levels, a phenotype resembling an interferonopathy. The Ser466Arg change affects a highly conserved residue located in the DNA binding domain of the protein and the amino acid substitution was documented to have an activating role both in vitro and in vivo. Altogether, clinical features and functional studies are compatible with hyperactivation of the Interferon pathways, highlighting a role of STAT1 GoF mutation in clinical phenotypes fitting interferonopathies.

AB - Signal Transducer and Activator of Transcription 1 (STAT1) is a DNA-binding signal transducer that regulates transcription of specific genes in response to IFNγ and IFNα/β stimulation. Loss-of-function mutations impairing STAT1 activity are known to confer susceptibility to intracellular bacterial and viral diseases. Conversely, the few known activating mutations of STAT1 allow predisposition to chronic mucocutaneous candidiasis disease, and occur in patients with combined immunodeficiency and defective Th1 and Th17 responses. Here, we report on a de novo gain-of-function (GoF) STAT1 mutation (c.1398C>G, p.Ser466Arg) identified by exome sequencing in an individual with brain calcification, arthritis, recurrent pericarditis, leukopenia, thrombocytopenia and low C3 levels, a phenotype resembling an interferonopathy. The Ser466Arg change affects a highly conserved residue located in the DNA binding domain of the protein and the amino acid substitution was documented to have an activating role both in vitro and in vivo. Altogether, clinical features and functional studies are compatible with hyperactivation of the Interferon pathways, highlighting a role of STAT1 GoF mutation in clinical phenotypes fitting interferonopathies.

U2 - 10.1111/cge.13632

DO - 10.1111/cge.13632

M3 - Article

C2 - 31448411

JO - Clinical Genetics

JF - Clinical Genetics

SN - 0009-9163

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