Science and Technology Production
Article
Authorship
Gutiérrez, Mariana Lilián
;
SCAGLIA, PAULA ALEJANDRA
;
Keselman, Ana Claudia
;
Martucci, Lucia Camila
;
Karabatas, Liliana Margarita
;
DOMENE, SABINA
;
MARTIN, AYELEN
;
PENNISI, PATRICIA ALEJANDRA
;
Blanco, Miguel
;
Sanguineti, Nora María
;
Bezrodnik, Liliana
;
Di Giovanni, Daniela
;
Caldirola, Maria Soledad
;
Esnaola Azcoiti, María
;
Gaillard, María Isabel
;
Denson, Lee A.
;
Zhang, Kejian
;
Husami, Ammar
;
Yayah Jones, Nana Hawa
;
Hwa, Vivian
;
Revale, Santiago
;
VAZQUEZ, MARTIN PABLO
;
Jasper, Hector Guillermo
;
Kumar, Ashish
;
Domene, Horacio Mario
Date
2018
Publishing House and Editing Place
Elsevier Ireland
Magazine
MOLECULAR AND CELLULAR ENDOCRINOLOGY.,
vol. 473
(pp. 166-177)
Elsevier Ireland
Summary
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Germinal heterozygous activating STAT3 mutations represent a novel monogenic defect associated with multi-organ autoimmune disease and, in some cases, severe growth retardation. By using whole-exome sequencing, we identified two novel STAT3 mutations, p.E616del and p.C426R, in two unrelated pediatric patients with IGF-I deficiency and immune dysregulation. The functional analyses showed that both variants were gain-of-function (GOF), although they were not constitutively phosphorylated. They pr...
Germinal heterozygous activating STAT3 mutations represent a novel monogenic defect associated with multi-organ autoimmune disease and, in some cases, severe growth retardation. By using whole-exome sequencing, we identified two novel STAT3 mutations, p.E616del and p.C426R, in two unrelated pediatric patients with IGF-I deficiency and immune dysregulation. The functional analyses showed that both variants were gain-of-function (GOF), although they were not constitutively phosphorylated. They presented differences in their dephosphorylation kinetics and transcriptional activities under interleukin-6 stimulation. Both variants increased their transcriptional activities in response to growth hormone (GH) treatment. Nonetheless, STAT5b transcriptional activity was diminished in the presence of STAT3 GOF variants, suggesting a disruptive role of STAT3 GOF variants in the GH signaling pathway. This study highlights the broad clinical spectrum of patients presenting activating STAT3 mutations and explores the underlying molecular pathway responsible for this condition, suggesting that different mutations may drive increased activity by slightly different mechanisms.
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Key Words
ACTIVATING MUTATIONSSTAT3IMMUNE DYSREGULATIONIGF-I DEFICIENCYGROWTH HORMONE INSENSITIVITY
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