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  • Author: Ángel Campos Barros x
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Angel Campos-Barros, Harald Meinhold, Barbara Walzog and Dietrich Behne

Abstract

Objective: The effects of single and combined nutritional selenium and iodine deficiency on intracellular thyroid hormone concentrations and type II 5′-iodothyronine deiodinase (5′D-II) activity were examined in different regions of the adult rat brain.

Design: Four groups (n=6) of weanling female Wistar rats proceeding from a breeding line fed a selenium-deficient or a selenium-replete diet for 3 generations, were fed selenium-deficient, iodine-deficient, combined selenium- and iodine-deficient or selenium- and iodine-replete diets for 2 months before they were killed.

Methods: Tissue thyroxine (T4) and tri-iodothyronine (T3) concentrations were determined by highly sensitive RIAs after extraction of the iodothyronines from the tissue samples. The measurement of 5′D-II was based on the release of radioiodide from the 125I-labelled substrate.

Results: Selenium deficiency significantly decreased tissue T3 concentrations in the hippocampus, hypothalamus and striatum to 70–80% of controls, whereas no significant changes were found in the cerebellum, cerebral cortex and brain stem. Tissue T4 concentrations were only marginally affected with the exception of a 35% increase in the cerebral cortex. Iodine deficiency dramatically diminished serum T4 levels as well as intracellular T4 concentrations in all regions examined up to 10–30% of control. In spite of a threefold enhancement of 5′D-II, the iodine-deficient animals still had a significant reduction of tissue T3 concentrations (50–65% of controls) in all regions excepting the cerebellum. The combination of selenium and iodine deficiency did not significantly alter this pattern of changes.

Conclusions: These findings suggest that prolonged selenium deficiency as well as iodine deficiency may compromise thyroid hormone homeostasis in the adult brain leading to tissue hypothyroidism and therefore to impaired brain function.

European Journal of Endocrinology 136 316–323

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Ana Claudia Keselman, Ayelen Martin, Paula Alejandra Scaglia, Nora María Sanguineti, Romina Armando, Mariana Gutiérrez, Débora Braslavsky, María Gabriela Ballerini, María Gabriela Ropelato, Laura Ramirez, Estefanía Landi, Sabina Domené, Julia F Castro, Hamilton Cassinelli, Bárbara Casali, Graciela del Rey, Ángel Campos Barros, Julián Nevado Blanco, Horacio Domené, Héctor Jasper, Claudia Arberas, Rodolfo A Rey, Pablo Lapunzina-Badía, Ignacio Bergadá and Patricia A Pennisi

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.