A Novel Mutation in Insulin-Like Growth Factor 1 Receptor (c.641-2A>G) Is Associated with Impaired Growth, Hypoglycemia, and Modified Immune Phenotypes

• Type of Material: Article
• Authors: Melanie R Shapiro, University of Florida; Timothy P Foster, University of Florida; Daniel J Perry, University of Florida; Ron G Rosenfeld, Oregon Hlth & Sci Univ; Andrew Dauber, Children’s National Hospital; James A McNichols, University of Florida; Andrew Muir, Emory University; Vivian Hwa, University of Cincinnati; Todd M Brusko, University of Florida; Laura M Jacobsen, University of Florida
• Language: English
• Date: 2020-12-01
• Publisher: KARGER
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 S. Karger AG, Basel
• Final Published Version (URL): http://dx.doi.org/10.1159/000510764
• Title of Journal or Parent Work: HORMONE RESEARCH IN PAEDIATRICS
• Volume: 93
• Issue: 5
• Start Page: 322
• End Page: 334
• Grant/Funding Information: Project support was provided by grants from the National Institutes of Health (F31 DK117548 to M.R.S.; P01 AI42288 to T.M.B.; R21HD98417 to V.H.).
• Keywords: HAPLOINSUFFICIENCY; PATIENT; FAMILIAL SHORT STATURE; IGF-I; Life Sciences & Biomedicine; FACTOR-I RECEPTOR; GENE; Science & Technology; Endocrinology & Metabolism; DEFECT; Hypoglycemia; Immunology; Growth; RETARDATION; Pediatrics; INTRAUTERINE; Insulin-like growth factor 1 receptor; CHILDREN

Abstract

Introduction: Insulin-like growth factor 1 receptor (IGF1R) mutations lead to systemic disturbances in growth and glucose homeostasis due to widespread IGF1R expression throughout the body. IGF1R is expressed by innate and adaptive immune cells, facilitating their development and exerting immunomodulatory roles in the periphery. Case Presentation: We report on a family presenting with a novel heterozygous IGF1R mutation with characterization of the mutation, IGF1R expression, and immune phenotyping. Twin probands presented clinically with short stature and hypoglycemia. Variable phenotypic expression was seen in 2 other family members carrying the IGF1R mutation. The probands were treated with exogenous growth hormone therapy and dietary cornstarch, improving linear growth and reducing hypoglycemic events. IGF1R c.641-2A>G caused abnormal mRNA splicing and premature protein termination. Flow cytometric immunophenotyping demonstrated lower IGF1R on peripheral blood mononuclear cells from IGF1R c.641-2A>G subjects. This alteration was associated with reduced levels of T-helper 17 cells and a higher percentage of T-helper 1 cells compared to controls, suggesting decreased IGF1R expression may affect CD4 Th-cell lineage commitment. Discussion: Collectively, these data suggest a novel loss-of-function mutation (c.641-2A>G) leads to aberrant mRNA splicing and IGF1R expression resulting in hypoglycemia, growth restriction, and altered immune phenotypes.