IMPE2023 Free Communications GH and IGFs 1 (4 abstracts)
Novel Insulin-Like Growth Factor 1 Gene Mutation: Broadening of The Phenotype and Implications for Insulin Resistance
Ayelen Martin* 1 , Claudio Giacomozzi* 2 , Maria Celia Fernández 1 , Mariana Gutiérrez 1 , Maria Iascone 3 , Horacio Domené 1 , Fernando Dominici 4 , Ignacio Bergadá 1 , Biagio Cangiano 5,6 , Luca Persani 7,8 & Patricia Pennisi 1
1Centro de Investigaciones Endocrinológicas "Dr. César Bergadá", CEDIE-CONICET-FEI-División de Endocrinología, Hospital de Niños Dr. R. Gutiérrez, Buenos Aires, Argentina. 2Unit of Pediatrics, Department of Maternal and Child Health, Carlo Poma Hospital, ASST, Mantua, Italy. 3Department of Medical Genetics, ASST Papa Giovanni XXIII, Bergamo, Italy. 4Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Biológica (IQUIFIB-CONICET), Buenos Aires, Argentina. 5Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy. 6Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy. 7Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy. 8Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
Purpose: Insulin-like Growth Factor (IGF)1 gene mutations are extremely rare causes of pre- and post-natal growth retardation. Phenotype can be heterogenous with varying degrees of neurosensory deafness, cognitive defects, glucose metabolism impairment and short stature. This study describes a 12.6-year-old girl presenting severe short stature and insulin resistance, but with normal hearing and neurological development at the lower limit of normal. Methods: DNA was obtained from the proband and both parents for whole exome sequencing (WES). In silico analysis was performed to predict the impact of the IGF1 variant on IGF1 and insulin receptors (IGF1R and IR) signalling. in vitro, HEK293 cells and HEK293cells expressing WT-IGF1 or Mut-IGF1 were used to assess the ability of each subject’s IGF1 to bind and activate IGF1R by phosphorylation studies and cell viability and apoptosis analyses. PC3 cells were used for siRNA transient IGF1R silencing experiments. Results: The proband had low immunoreactive IGF1 in serum and WES revealed a novel homozygous IGF1 missense variant (c.247A>T), causing a change of serine 83 for cysteine (p.Ser83Cys; p.Ser35Cys in mature peptide). The proband’s parents were heterozygous for this mutation. In silico analyses indicated the pathogenic potential of the variant with electrostatic variations with the potential of hampering the interaction with the IGF1R but strengthening the binding to IR. The mutant IGF1 protein had a significantly reduced activity on in vitro bioassays. In vitro phosphorylation of IR in the presence of mutant IGF1 was not impaired. On the contrary, we observed a tendency towards the increase of insulin receptor phosphorylation in the presence of p.S35C-IGF1. Also, IR expression was not modified after chronic exposure to p.S35C-IGF1. Main conclusions: We describe a novel IGF1mutation leading to severe loss of circulating IGF1 immunoreactivity and bioactivity. In silico modelling predicts that the mutant IGF1 could interfere with IR signalling, providing a possible explanation for the severe insulin resistance observed in the patient. The absence of significant hearing and neurodevelopmental involvement in the present case is unusual and broadens the clinical spectrum of IGF1 mutations
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