Novel insulin-like growth factor 1 gene mutation: broadening of the phenotype and implications for insulin resistance

AYELEN MARTIN; CLAUDIO GIACOMOZZI; MARÍA CELIA FERNANDEZ; MARIANA GUTIÉRREZ; MARIA IASCONE; HORACIO DOMENÉ; FERNANDO DOMINICI; IGNACIO BERGADÁ; BIAGIO CANGIANO; LUCA PERSANI; PATRICIA PENNISI

Buenos Aires

Congreso; 11th International Meeting of Paediatric Endocrinology (IMPE); 2023

Purpose: Insulin-like Growth Factor (IGF)1 gene mutations areextremely rare causes of pre- and post-natal growth retardation.Phenotype can be heterogenous with varying degrees of neurosensorydeafness, cognitive defects, glucose metabolism impairment and short stature. This study describes a 12.6-year-old girl presentingsevere short stature and insulin resistance, but with normal hearingand neurological development at the lower limit of normal.Methods: DNA was obtained from the proband and both parentsfor whole exome sequencing (WES). In silico analysis was performedto predict the impact of the IGF1 variant on IGF1 and insulinreceptors (IGF1R and IR) signalling. In vitro, HEK293 cells andHEK293cells expressing WT-IGF1 or Mut-IGF1 were used to assessthe ability of each subject’s IGF1 to bind and activate IGF1R by phosphorylationstudies and cell viability and apoptosis analyses. PC3cells were used for siRNA transient IGF1R silencing experiments.Results: The proband had low immunoreactive IGF1 in serumand 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 heterozygousfor this mutation. In silico analyses indicated the pathogenicpotential of the variant with electrostatic variations withthe potential of hampering the interaction with the IGF1R butstrengthening the binding to IR. The mutant IGF1 protein had asignificantly reduced activity on in vitro bioassays. In vitro phosphorylationof IR in the presence of mutant IGF1 was not impaired.On the contrary, we observed a tendency towards the increase ofinsulin receptor phosphorylation in the presence of p.S35C-IGF1.Also, IR expression was not modified after chronic exposure top.S35C-IGF1.Main Conclusions: We describe a novel IGF1 mutation leadingto severe loss of circulating IGF1 immunoreactivity and bioactivity.In silico modelling predicts that the mutant IGF1 could interferewith IR signalling, providing a possible explanation for thesevere insulin resistance observed in the patient. The absence ofsignificant hearing and neurodevelopmental involvement in thepresent case is unusual and broadens the clinical spectrum of IGF1mutations.