{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:31:39Z","timestamp":1790857899681,"version":"4.1.0"},"reference-count":36,"publisher":"The Endocrine Society","issue":"6","license":[{"start":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T00:00:00Z","timestamp":1671580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Italian Ministry of University and Research"},{"name":"Rome and Istituto Auxologico Italiano"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The proband had low immunoreactive IGF1 in serum and WES revealed a novel homozygous IGF1 missense variant (c.247A&amp;gt;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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgac738","type":"journal-article","created":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T10:16:04Z","timestamp":1671704164000},"page":"1355-1369","source":"Crossref","is-referenced-by-count":11,"title":["Novel Insulin-Like Growth Factor 1 Gene Mutation: Broadening of the Phenotype and Implications for Insulin Resistance"],"prefix":"10.1210","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6222-1755","authenticated-orcid":false,"given":"Claudio","family":"Giacomozzi","sequence":"first","affiliation":[{"name":"Unit of Pediatrics, Department of Maternal and Child Health, Carlo Poma Hospital, ASST-Mantova , 46100 Mantua , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayelen","family":"Martin","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Endocrinol\u00f3gicas \u2018Dr. C\u00e9sar Bergad\u00e1\u2019 (CEDIE) CONICET\u2014FEI\u2014Divisi\u00f3n de Endocrinolog\u00eda, Hospital de Ni\u00f1os Dr. Ricardo Guti\u00e9rrez , C1425EFD Buenos Aires , Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Celia","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Endocrinol\u00f3gicas \u2018Dr. C\u00e9sar Bergad\u00e1\u2019 (CEDIE) CONICET\u2014FEI\u2014Divisi\u00f3n de Endocrinolog\u00eda, Hospital de Ni\u00f1os Dr. Ricardo Guti\u00e9rrez , C1425EFD Buenos Aires , Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Endocrinol\u00f3gicas \u2018Dr. C\u00e9sar Bergad\u00e1\u2019 (CEDIE) CONICET\u2014FEI\u2014Divisi\u00f3n de Endocrinolog\u00eda, Hospital de Ni\u00f1os Dr. Ricardo Guti\u00e9rrez , C1425EFD Buenos Aires , Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4707-212X","authenticated-orcid":false,"given":"Maria","family":"Iascone","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, ASST Papa Giovanni XXIII , 24127 Bergamo , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horacio M","family":"Domen\u00e9","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Endocrinol\u00f3gicas \u2018Dr. C\u00e9sar Bergad\u00e1\u2019 (CEDIE) CONICET\u2014FEI\u2014Divisi\u00f3n de Endocrinolog\u00eda, Hospital de Ni\u00f1os Dr. Ricardo Guti\u00e9rrez , C1425EFD Buenos Aires , Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando P","family":"Dominici","sequence":"additional","affiliation":[{"name":"Universidad de Buenos Aires, Facultad de Farmacia y Bioqu\u00edmica, Departamento de Qu\u00edmica Biol\u00f3gica (IQUIFIB-CONICET) , 1113AAB Buenos Aires , Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Bergad\u00e1","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Endocrinol\u00f3gicas \u2018Dr. C\u00e9sar Bergad\u00e1\u2019 (CEDIE) CONICET\u2014FEI\u2014Divisi\u00f3n de Endocrinolog\u00eda, Hospital de Ni\u00f1os Dr. Ricardo Guti\u00e9rrez , C1425EFD Buenos Aires , Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2658-744X","authenticated-orcid":false,"given":"Biagio","family":"Cangiano","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan , 20100 Milan , Italy"},{"name":"Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano , 20100 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2068-9581","authenticated-orcid":false,"given":"Luca","family":"Persani","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan , 20100 Milan , Italy"},{"name":"Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano , 20100 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5179-7353","authenticated-orcid":false,"given":"Patricia A","family":"Pennisi","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Endocrinol\u00f3gicas \u2018Dr. C\u00e9sar Bergad\u00e1\u2019 (CEDIE) CONICET\u2014FEI\u2014Divisi\u00f3n de Endocrinolog\u00eda, Hospital de Ni\u00f1os Dr. Ricardo Guti\u00e9rrez , C1425EFD Buenos Aires , Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2022,12,21]]},"reference":[{"issue":"1","key":"2023051701083414500_dgac738-B1","first-page":"59","article-title":"Mice carrying null mutations of the genes encoding insulin-like growth factor I (IGF-1) and type 1 IGF receptor (Igf1r)","volume":"75","author":"Liu","year":"1993","journal-title":"Cell"},{"issue":"4","key":"2023051701083414500_dgac738-B2","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/0896-6273(95)90216-3","article-title":"Igf1 gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons","volume":"14","author":"Beck","year":"1995","journal-title":"Neuron"},{"issue":"5","key":"2023051701083414500_dgac738-B3","first-page":"1548","article-title":"Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth","volume":"80","author":"Giudice","year":"1995","journal-title":"J Clin Endocrinol Metab"},{"issue":"18","key":"2023051701083414500_dgac738-B4","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1056\/NEJM199610313351805","article-title":"Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene","volume":"335","author":"Woods","year":"1996","journal-title":"N Engl J Med"},{"issue":"12","key":"2023051701083414500_dgac738-B5","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1136\/jmg.40.12.913","article-title":"A novel mutation in a patient with insulin-like growth factor 1 (IGF1) deficiency","volume":"40","author":"Bonapace","year":"2003","journal-title":"J Med Genet"},{"key":"2023051701083414500_dgac738-B6","doi-asserted-by":"crossref","DOI":"10.1016\/j.mce.2020.111035","article-title":"Disorders of IGFs and IGF-1R signaling pathways","volume":"518","author":"Forbes","year":"2020","journal-title":"Mol Cell Endocrinol"},{"issue":"5","key":"2023051701083414500_dgac738-B7","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.1210\/jc.2004-1254","article-title":"Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation","volume":"90","author":"Walenkamp","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"issue":"10","key":"2023051701083414500_dgac738-B8","doi-asserted-by":"crossref","first-page":"3913","DOI":"10.1210\/jc.2009-0452","article-title":"Partial primary deficiency of insulin-like growth factor (IGF)-I activity associated with IGF1 mutation demonstrates its critical role in growth and brain development","volume":"94","author":"Netchine","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"2023051701083414500_dgac738-B9","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1530\/EJE-19-0563","article-title":"A homozygous mutation in the highly conserved Tyr60 of the mature IGF1 peptide broadens the spectrum of IGF1 deficiency","volume":"181","author":"Keselman","year":"2019","journal-title":"Eur J Endocrinol"},{"issue":"4","key":"2023051701083414500_dgac738-B10","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1210\/jcem.85.4.6495","article-title":"Effects of insulin-like growth factor I (IGF-I) therapy on body composition and insulin resistance in IGF-I gene deletion","volume":"85","author":"Woods","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2023051701083414500_dgac738-B11","first-page":"317","volume-title":"The Measurement of Human Growth","author":"Cameron","year":"1984:"},{"issue":"3","key":"2023051701083414500_dgac738-B12","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1097\/MPG.0b013e3181da213e","article-title":"Neonatal anthropometric charts: the Italian neonatal study compared with other European studies","volume":"51","author":"Bertino","year":"2010","journal-title":"J Pediatr Gastroenterol Nutr"},{"issue":"7","key":"2023051701083414500_dgac738-B13","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/BF03344156","article-title":"Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr)","volume":"29","author":"Cacciari","year":"2006","journal-title":"J Endocrinol Invest"},{"issue":"3","key":"2023051701083414500_dgac738-B14","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1136\/adc.51.3.170","article-title":"Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty","volume":"51","author":"Tanner","year":"1976","journal-title":"Arch Dis Child"},{"issue":"1","key":"2023051701083414500_dgac738-B15","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1186\/1471-2393-14-157","article-title":"WHO multicentre study for the development of growth standards from fetal life to childhood: the fetal component","volume":"14","author":"Merialdi","year":"2014","journal-title":"BMC Pregnancy Childbirth"},{"issue":"3","key":"2023051701083414500_dgac738-B16","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1002\/ajpa.1330350306","article-title":"Attributes of the radiographic standard of reference for the national health examination survey","volume":"35","author":"Pyle","year":"1971","journal-title":"Am J Phys Anthropol"},{"issue":"11","key":"2023051701083414500_dgac738-B17","first-page":"3990","article-title":"Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH research society1","volume":"85","author":"Growth Hormone Research Society","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2023051701083414500_dgac738-B18","doi-asserted-by":"crossref","first-page":"e1064","DOI":"10.1002\/mgg3.1064","article-title":"Double homozygosity in CEP57 and DYNC2H1 genes detected by WES: composite or expanded phenotype?","volume":"8","author":"Pezzani","year":"2020","journal-title":"Mol Genet Genomic Med"},{"issue":"10","key":"2023051701083414500_dgac738-B19","doi-asserted-by":"crossref","first-page":"1105-","DOI":"10.1038\/gim.2017.37","article-title":"Sherloc: A comprehensive refinement of the ACMG-AMP variant classification criteria","volume":"19","author":"Nykamp","year":"2017","journal-title":"Genet Med"},{"issue":"5","key":"2023051701083414500_dgac738-B20","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"issue":"13","key":"2023051701083414500_dgac738-B21","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J Comput Chem"},{"issue":"35","key":"2023051701083414500_dgac738-B22","doi-asserted-by":"crossref","first-page":"20424","DOI":"10.1074\/jbc.270.35.20424","article-title":"Studies on the mechanisms by which insulin-like growth factor (IGF) binding protein-4 (IGFBP-4) and IGFBP-5 modulate IGF actions in bone cells","volume":"270","author":"Mohan","year":"1995","journal-title":"J Biol Chem"},{"issue":"8","key":"2023051701083414500_dgac738-B23","doi-asserted-by":"crossref","first-page":"3724","DOI":"10.1210\/en.2012-1107","article-title":"Igf-I regulates pheochromocytoma cell proliferation and survival in vitro and in vivo","volume":"153","author":"Fernandez","year":"2012","journal-title":"Endocrinology"},{"issue":"3","key":"2023051701083414500_dgac738-B24","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s12672-018-0328-7","article-title":"Type 1 IGF receptor localization in paediatric gliomas: significant association with WHO grading and clinical outcome","volume":"9","author":"Cl\u00e9ment","year":"2018","journal-title":"Horm Cancer"},{"issue":"1","key":"2023051701083414500_dgac738-B25","doi-asserted-by":"crossref","first-page":"5034","DOI":"10.1038\/s41598-020-61695-8","article-title":"Genetic landscape of autism spectrum disorder in Vietnamese children","volume":"10","author":"Tran","year":"2020","journal-title":"Sci Rep"},{"issue":"2","key":"2023051701083414500_dgac738-B26","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1101\/gr.160572.113","article-title":"Genomic analysis of primordial dwarfism reveals novel disease genes","volume":"24","author":"Shaheen","year":"2014","journal-title":"Genome Res"},{"issue":"3","key":"2023051701083414500_dgac738-B27","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/s41436-018-0140-3","article-title":"Genomic and phenotypic delineation of congenital microcephaly","volume":"21","author":"Shaheen","year":"2019","journal-title":"Genet Med"},{"issue":"7","key":"2023051701083414500_dgac738-B28","doi-asserted-by":"crossref","first-page":"4419","DOI":"10.1074\/jbc.R111.275578","article-title":"Analysis and functional prediction of reactive cysteine residues","volume":"287","author":"Marino","year":"2012","journal-title":"J Biol Chem"},{"issue":"14","key":"2023051701083414500_dgac738-B29","doi-asserted-by":"crossref","first-page":"10609","DOI":"10.1016\/S0021-9258(17)34103-0","article-title":"Positively charged side chains in the insulin-like growth factor-1 C- and D-regions determine receptor binding specificity","volume":"269","author":"Zhang","year":"1994","journal-title":"J Biol Chem"},{"issue":"11","key":"2023051701083414500_dgac738-B30","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1093\/protein\/9.11.1011","article-title":"Engineering the C-region of human insulin-like growth factor-1: implications for receptor binding","volume":"9","author":"Gill","year":"1996","journal-title":"Protein Eng"},{"issue":"1","key":"2023051701083414500_dgac738-B31","doi-asserted-by":"crossref","first-page":"4567","DOI":"10.1038\/s41467-019-12564-0","article-title":"Structural basis of the activation of type 1 insulin-like growth factor receptor","volume":"10","author":"Li","year":"2019","journal-title":"Nat Commun"},{"issue":"33","key":"2023051701083414500_dgac738-B32","doi-asserted-by":"crossref","first-page":"12429","DOI":"10.1073\/pnas.0605395103","article-title":"The first three domains of the insulin receptor differ structurally from the insulin-like growth factor 1 receptor in the regions governing ligand specificity","volume":"103","author":"Lou","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2023051701083414500_dgac738-B33","author":"Giacomozzi"},{"issue":"3","key":"2023051701083414500_dgac738-B34","doi-asserted-by":"crossref","first-page":"239","DOI":"10.3390\/genes11030239","article-title":"Genetic modifiers and rare Mendelian disease","volume":"11","author":"Rahit","year":"2020;","journal-title":"Genes (Basel)"},{"issue":"1","key":"2023051701083414500_dgac738-B35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13148-020-00911-8","article-title":"What impact does oocyte vitrification have on epigenetics and gene expression?","volume":"12","author":"Barberet","year":"2020","journal-title":"Clin Epigenetics"},{"issue":"2","key":"2023051701083414500_dgac738-B36","doi-asserted-by":"crossref","DOI":"10.1210\/endocr\/bqab251","article-title":"Identification of novel regulatory regions induced by intrauterine growth restriction in rat islets","volume":"163","author":"Lien","year":"2022","journal-title":"Endocrinology"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgac738\/48591597\/dgac738.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/108\/6\/1355\/50355157\/dgac738.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/108\/6\/1355\/50355157\/dgac738.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T01:09:48Z","timestamp":1684285788000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/108\/6\/1355\/6955787"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,21]]},"references-count":36,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,12,21]]},"published-print":{"date-parts":[[2023,5,17]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgac738","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,6]]},"published":{"date-parts":[[2022,12,21]]}}}