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

Abstract

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.

Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

“…98 Discovery of more than 20 new patients followed shortly thereafter. 99,100,[115][116][117][118][119] Autoimmune disease, multisystem, infantile-onset syndrome (ADMIO, also known as STAT3 GOF disease, which is caused by a GOF mutation in STAT3 gene) usually manifests early in infancy or childhood and is presented commonly with diarrhea, enteropathy, autoimmune cytopenias, lymphoproliferation, interstitial lung disease, recurrent infections with various pathogen species, eczema, short stature, and T1D; while less commonly with hypothyroidism, arthritis, hepatitis, and malignancies (Hodgkin lymphoma, T-cell large granular lymphocyte leukemia, and squamous cell carcinoma). Germline GOF STAT3 mutations are found across the entire gene and do not seem to correlate with the patient phenotype.…”

“…98,120 Unlike in patients with STAT1 GOF disease, some GOF mutations in STAT3 did not affect its baseline phosphorylation but increased its transcriptional activity. 100 Dysregulation in B-cell subsets and immunoglobulin levels was frequently observed but highly variable; several patients exhibited lower levels of class-switched immunoglobulin (IgG and IgA) and numbers of memory B cells, 99,100,[115][116][117][118] indicating a potential impairment in B-cell antigen responses. Many, but not all, patients had decreased frequencies of FOXP3 1 Treg cells, and loss of suppressive function has been reported in some patients.…”

“…98,99,116,117 Lymphoproliferation was accompanied by an increase in the frequency of circulating double-negative CD3 1 CD8 2 CD4 2 T cells and defective Fas-mediated apoptosis. 100,117 Several patients had low T H 17 numbers, 99,115 and others had normal or even increased T H 17 responses. 119 The STAT3 signaling cascade involves multiple proteins that regulate Treg and T H 17 cells.…”

Update on new GH-IGF axis genetic defects

“…Although mutated STAT3 were not constitutively phosphorylated, they presented delayed dephosphorylation, leading to enhanced activity. Additionally, under unstimulated conditions and under GH treatment, both GOF STAT3 variants decreased STAT5B transcriptional activity, suggesting a negative impact in the GH signaling pathway (41).…”

Genetics and genomic medicine in Argentina

“…Finally, we would like to remark that several research/ clinical groups are using genomic approaches for the study and diagnosis of genetic disorders such as neurological disorders (Cordoba et al, 2018;Rodriguez-Quiroga et al, 2015), Duchenne/Becker muscular dystrophy (Luce et al, 2018), breast cancer (Solano et al, 2017, ovarian cancer (Cardoso et al, 2018), and endocrine/immune diseases (Gutierrez et al, 2018), among others.…”