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.

Asunto(s)

Células Germinativas/metabolismo , Trastornos del Crecimiento/genética , Pérdida Auditiva Sensorineural/genética , Enfermedades del Sistema Inmune/genética , Factor I del Crecimiento Similar a la Insulina/deficiencia , Mutación/genética , Factor de Transcripción STAT3/genética , Secuencia de Aminoácidos , Preescolar , Femenino , Células HEK293 , Hormona de Crecimiento Humana/farmacología , Humanos , Lactante , Recién Nacido , Factor I del Crecimiento Similar a la Insulina/genética , Interleucina-5/metabolismo , Luciferasas/metabolismo , Masculino , Modelos Moleculares , Fosforilación/efectos de los fármacos , Multimerización de Proteína , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/química , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/genética , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Transcripción Genética/efectos de los fármacos , Secuenciación del Exoma