Partial growth hormone insensitivity and dysregulatory immune disease associated with de novo germline activating STAT3 mutations

Publication date: Available online 3 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Mariana Gutiérrez, Paula Scaglia, Ana Keselman, Lucía Martucci, Liliana Karabatas, Sabina Domené, Ayelen Martin, Patricia Pennisi, Miguel Blanco, Nora Sanguineti, Liliana Bezrodnik, Daniela Di Giovanni, María Soledad Caldirola, María Esnaola Azcoiti, María Isabel Gaillard, Lee A. Denson, Kejian Zhang, Ammar Husami, Nana-Hawa Yayah Jones, Vivian Hwa, Santiago Revale, Martín Vázquez, Héctor Jasper, Ashish Kumar, Horacio Domené
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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