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; MARÍA IASCONE; HORACIO DOMENÉ; IGNACIO BERGADÁ; PATRICIA PENNISI; BIAGIO CANGIANO; LUCA PERSANI

Bogotá

Congreso; XXXth Annual Meeting of the Latin American Pediatric Endocrinology Society (SLEP); 2022

Introduction: 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 ofneurosensory deafness, cognitive defects, glucose metabolismimpairment and short stature.Objective: This study describes a 12.6-year-old girl presentingsevere 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 wasperformed to predict the impact of the IGF1 variant on IGF1 andinsulin receptors (IGF1R and IR) signalling. In vitro, HEK293 cellsand HEK293cells expressing WT-IGF1 or Mut-IGF1 were used toassess the ability of each subject’s IGF1 to bind and activate IGF1Rby phosphorylation studies and cell viability and apoptosis analyses. PC3 cells were used for siRNA transient IGF1R silencingexperiments.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 heterozygous for this mutation. In silico analyses indicated the pathogenic potential of the variant with electrostatic variations with thepotential 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 phosphorylation of 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.Conclusion: In conclusion, we describe the second case of partial IGF1 deficiency due to a missense mutation located in theC-domain of pIGF1, but the first with an early severe impairmentof glucose homeostasis expanding the phenotype of this rare disease. We have explored and described in detail the effect of thevariant on IGF1R activation, demonstrating how partial IGF1 deficiency might be misdiagnosed due to non-classical phenotype andunreliable IGF1 assessments. Furthermore, we provide new insighton the potential pathogenesis of insulin resistance and glucoseintolerance in patients with particular IGF1 mutations.