A homozygous mutation in the highly conserved Tyr60 of the mature IGF1 peptide broadens the spectrum of IGF1 deficiency
| Autor: | Pablo Lapunzina-Badía, Sabina Domene, Angel Campos Barros, Hector Jasper, Julia F Castro, Laura Ramirez, Ayelen Martin, Claudia Arberas, Barbara Casali, Julián Nevado Blanco, María Gabriela Ropelato, Estefania Landi, Debora Braslavsky, Ignacio Bergadá, Patricia Pennisi, Romina Armando, Ana Keselman, María Gabriela Ballerini, Mariana Gutierrez, Rodolfo Rey, Paula Scaglia, Graciela Del Rey, Horacio M. Domené, Nora Sanguineti, Hamilton Cassinelli |
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| Rok vydání: | 2019 |
| Předmět: |
endocrine system
medicine.medical_specialty Microcephaly Endocrinology Diabetes and Metabolism IGFBP3 Intrauterine growth restriction 030209 endocrinology & metabolism General Medicine Gene mutation Biology medicine.disease Short stature 03 medical and health sciences 0302 clinical medicine Endocrinology 030220 oncology & carcinogenesis Internal medicine medicine Small for gestational age Missense mutation medicine.symptom hormones hormone substitutes and hormone antagonists SNP array |
| Zdroj: | European Journal of Endocrinology. 181:K43-K53 |
| ISSN: | 1479-683X 0804-4643 |
| DOI: | 10.1530/eje-19-0563 |
| Popis: | Background IGF1 is a key factor in fetal and postnatal growth. To date, only three homozygous IGF1 gene defects leading to complete or partial loss of IGF1 activity have been reported in three short patients born small for gestational age. We describe the fourth patient with severe short stature presenting a novel homozygous IGF1 gene mutation. Results We report a boy born from consanguineous parents at 40 weeks of gestational age with intrauterine growth restriction and severe postnatal growth failure. Physical examination revealed proportionate short stature, microcephaly, facial dysmorphism, bilateral sensorineural deafness and mild global developmental delay. Basal growth hormone (GH) fluctuated from 0.2 to 29 ng/mL, while IGF1 levels ranged from −1.15 to 2.95 SDS. IGFBP3 was normal-high. SNP array delimited chromosomal regions of homozygosity, including 12q23.2 where IGF1 is located. IGF1 screening by HRM revealed a homozygous missense variant NM_000618.4(IGF1):c.322T>C, p.(Tyr108His). The change of the highly conserved Tyr60 in the mature IGF1 peptide was consistently predicted as pathogenic by multiple bioinformatic tools. Tyr60 has been described to be critical for IGF1 interaction with type 1 IGF receptor (IGF1R). In vitro, HEK293T cells showed a marked reduction of IGF1R phosphorylation after stimulation with serum from the patient as compared to sera from age-matched controls. Mutant IGF1 was also less efficient in inducing cell growth. Conclusion The present report broadens the spectrum of clinical and biochemical presentation of homozygous IGF1 defects and underscores the variability these patients may present depending on the IGF/IGF1R pathway activity. |
| Databáze: | OpenAIRE |
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