info:eu-repo/semantics/article
Partial growth hormone insensitivity and dysregulatory immune disease associated with de novo germline activating STAT3 mutations
Fecha
2018-09Registro en:
Gutiérrez, Mariana Lilián; Scaglia, Paula Alejandra; Keselman, Ana Claudia; Martucci, Lucia Camila; Karabatas, Liliana Margarita; et al.; Partial growth hormone insensitivity and dysregulatory immune disease associated with de novo germline activating STAT3 mutations; Elsevier Ireland; Molecular and Cellular Endocrinology; 473; 9-2018; 166-177
0303-7207
CONICET Digital
CONICET
Autor
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
Resumen
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.