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Cited by 10Growth Hormone and Insulin-like Growth FactorsGenomics and Rare DiseasesConnective tissue disorders research

The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index.

Novel Insulin-Like Growth Factor 1 Gene Mutation: Broadening of the Phenotype and Implications for Insulin Resistance

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Giacomozzi, Claudio, Martin, Ayelen, Fernández, María Celia, Gutiérrez, Mariana, Iascone, Maria, Domené, Horacio M, Dominici, Fernando P, Bergadá, Ignacio, Cangiano, Biagio, Persani, Luca, Pennisi, Patricia A·2023·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/clinem/dgac738
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Abstract

CONTEXT: Insulin-like growth factor (IGF)1 gene mutations are extremely rare causes of pre- and postnatal growth retardation. Phenotype can be heterogenous with varying degrees of neurosensory deafness, cognitive defects, glucose metabolism impairment and short stature. OBJECTIVE: This study describes a 12.6-year-old girl presenting with 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) signaling. Phosphorylation of the IGF1R at activating Tyr residues and cell proliferation analyses were used to assess the ability of each subject's IGF1 to bind and activate IGF1R. 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. CONCLUSION: We describe a novel IGF1 mutation leading to severe loss of circulating IGF1 immunoreactivity and bioactivity. In silico modeling predicts that the mutant IGF1 could interfere with IR signaling, 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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  • The activity of IGF-1/IGFR that elevates PI3K/Akt/mTor has been shown to act against longevity in animal and human studies.

    “The activity of IGF-1/IGFR that elevates PI3K/Akt/mTor has been shown to act against longevity in animal [110] and human studies [111,112].”

    From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [112]

    The citation is attached to the human-studies portion of the sentence. Our copy reports reduced IGF1R phosphorylation with a mutant IGF1 protein (IGF1R phosphorylation and proliferation section; page unavailable), but the passages found when searching for longevity, lifespan, PI3K/Akt, and mTOR do not address whether IGF1/IGF1R activity acts against human longevity. (LLM, conf=0.74)

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Metadata

Authors
Giacomozzi, C., Martin, A., Fernández, M. C., Gutiérrez, M., Iascone, M., Domené, H. M., Dominici, F. P., Bergadá, I., Cangiano, B., Persani, L., & Pennisi, P. A.
Affiliations
  • Azienda Ospedaliera Carlo Poma (IT)
  • Centro de Investigaciones Endocrinológicas ‘Dr. César Bergadá’ (CEDIE) CONICET—FEI—División de Endocrinología, Hospital de Niños Dr. Ricardo Gutiérrez , C1425EFD Buenos Aires , Argentina
  • Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
  • Ospedale Papa Giovanni XXIII (IT)
  • University of Milan (IT)
Corresponding author
Giacomozzi, Claudio
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2022-12-21
Volume
108
Issue
6
Pages
1355-1369
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/clinem/dgac738
OpenAlex
W4312095345
Cited by
10
References
36
Citations by year
2026: 1 · 2025: 4 · 2024: 3 · 2023: 2
FWCI
1.67
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Italian Ministry of University and Research
  • Rome and Istituto Auxologico Italiano
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
Keywords
insulin-like growth factor I, novel missense mutation, insulin resistance, short stature, IGF1R signaling, insulin receptor signaling, variant pathogenicity prediction, growth retardation
MeSH terms
Dwarfism, Humans, Insulin Resistance, Insulin-Like Growth Factor I, Mutation, Phenotype, Receptor, IGF Type 1, Mutation, Missense

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