Growth Hormone (GH) Insensitivity and Insulin-Like Growth Factor-I Deficiency in Inuit Subjects and an Ecuadorian Cohort: Functional Studies of Two Codon 180 GH Receptor Gene Mutations

Peng, Fang; Girgis, Rose; Little, Brian M.; Pratt, Katherine L.; Guevara‐Aguirre, Jaime; Hwa, Vivian; Rosenfeld, Ron G.

doi:10.1210/jc.2007-2022

Cited by 23 publications

(14 citation statements)

References 33 publications

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“…We first tested mechanisms underlying the protective effects of GH signaling deficiency. We examined primary skin fibroblasts derived from short-stature GHR mut Laron syndrome subjects harboring an inactivating GHR mutation, and which are defective in GH signaling (44). When actively proliferating asynchronized cells were pulsed with BrdU, incorporation was 40% lower in mutated than in WT fibroblasts (Fig.…”

Section: Resultsmentioning

confidence: 99%

Growth hormone is permissive for neoplastic colon growth

Chesnokova

Zonis

Zhou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

103

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Fig. 6. GH induces EMT, suppresses apoptosis, and increases motility. Western blot analysis of PTEN and EMT factors in (A) hNCC and (B) HCT116 cells treated with indicated doses of GH for 24 h. (C) Western blot analysis of cleaved caspase 3 in cells treated with GH (500 ng/mL) for 24 h. Experiments were performed at least three times, and representative results shown. (D) Migration of hNCC and HCT116 cells treated with GH (500 ng/mL) and harvested 48 h after plating. (E) Migration of HCT116 cocultured for 48 h with hCF infected with lentivector or lentiGH. In D and E, for quantification, the number of migrated cells per 1,000 cells in five randomly chosen fields in each duplicate transwell were counted and means calculated. Results are presented as mean ± SEM of three independent experiments; *P < 0.05. (F) Number of colonies and arbitrary colony size formed in soft agar by HCT116 cells cocultured with hCF infected with lentivector or lentiGH, and tested for anchorage independent growth. Colony size was determined using ImageJ software. Results are presented as mean ± SEM of duplicates from two independent experiments; **P < 0.01 vs. control. In D-F, the differences between groups were analyzed using two-tailed unpaired Student t test.

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Section: Resultsmentioning

confidence: 99%

Growth hormone is permissive for neoplastic colon growth

Chesnokova

Zonis

Zhou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

103

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“…This variant was inherited from their unaffected parents and has been described previously [19]. Both children had a classical clinical phenotype of Laron syndrome with midface hypoplasia, prominent forehead, severe short stature, and exhibited severe GH insensitivity (see Table 1).…”

Section: Resultsmentioning

confidence: 99%

Targeted Resequencing of Putative Growth-Related Genes Using Whole Exome Sequencing in Patients with Severe Primary IGF-I Deficiency

et al. 2017

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Background/Aims: To elucidate the genetic causes of severe primary insulin-like growth factor-I deficiency (SPIGFD) by systematic, targeted, next-generation sequencing (NGS)-based resequencing of growth-related genes. Methods: Clinical phenotyping followed by NGS in 17 families including 6 affected sib pairs. Results: We identified disease-causing, heterozygous, de novo variants in HRAS (p.Gly13Cys) and FAM111A (p.Arg569His) in 2 male patients with syndromic SPIGFD. A previously described homozygous GHR nonsense variant was detected in 2 siblings of a consanguineous family (p.Glu198*). Furthermore, we identified an inherited novel variant in the IGF2 gene (p.Arg156Cys) of a maternally imprinted gene in a less severely affected father and his affected daughter. We detected 2 other novel missense variants in SH2B1 and SOCS2, both were inherited from an unaffected parent. Conclusions: Screening of growth-related genes using NGS-based, large-scale, targeted resequencing identified disease-causing variants in HRAS, FAM111A, and GHR. Considering the increased risk of subjects with HRAS mutations for neoplasms, close clinical monitoring and a thorough discussion of the risk/benefit ratio of the treatment with recombinant IGF-I is mandatory. Segregation analysis proved to be critical in the interpretation of potential SPIGFD-associated gene variations.

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“…For transfection experiments, HEK293-T cells were seeded at a density of 2 × 10 5 cells/well in a 24-multi well plate, grown to approximately 70–90% confluence, and transiently transfected with 500 ng Empty-pCMV6, or with a combination of 250 ng pcDNAI_Amp-GHRfl (Fang et al, 2008) and 250 ng vector carrying WT-STAT3 or variants using Lipofectamine 3000 reagent (Invitrogen, Carlsbad, CA, USA). After 24 h transfection, cells were washed and serum starved for 6 h before a 15, 30 or 120-min treatment with 200 ng/mL recombinant human (rh) GH (Sandoz, Olivos, Argentina) or 20 ng/mL IL-6 (Gibco, Grand Island, NY, USA).…”

Section: Methodsmentioning

confidence: 99%

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

Gutiérrez

Scaglia

Keselman

et al. 2018

Molecular and Cellular Endocrinology

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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 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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Growth Hormone (GH) Insensitivity and Insulin-Like Growth Factor-I Deficiency in Inuit Subjects and an Ecuadorian Cohort: Functional Studies of Two Codon 180 GH Receptor Gene Mutations

Abstract: The E180X mutation identified in two Inuit patients resulted in a truncated, unstably expressed GHR variant, whereas the E180 splicing mutation previously identified in the Ecuadorian cohort, affected both GH binding and GHR trafficking and rendered the abnormal GHR nonfunctional.

Cited by 23 publications

References 33 publications

Growth hormone is permissive for neoplastic colon growth

Growth hormone is permissive for neoplastic colon growth

Targeted Resequencing of Putative Growth-Related Genes Using Whole Exome Sequencing in Patients with Severe Primary IGF-I Deficiency

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

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