Abstracts: 42nd Annual Meeting of the European Thyroid Association. Budapest, Hungary. September 7–10, 2019
Year: 2019
Type: conference-abstract
Abstract: Selenium is incorporated as selenocysteine (Sec) into a family of selenoproteins (SPs) with diverse, biological roles.Sec incorporation is mediated by a multiprotein-complex including SECIS-binding protein-2 (SBP2).Individuals with biallelic SBP2 mutations exhibit a multisystem disorder with growth retardation, abnormal thyroid hormone metabolism (high T4, normal or low T3, high rT3 and normal TSH) due to deficiency of Sec-containing deiodinases, phenotypes (e.g.muscular dystrophy, male infertility) mediated by lack of tissue-specific selenoproteins and tissue oxidative damage due to loss of antioxidant selenoenzymes.Most recently, a complex aortopathy consisting of dilatation of aortic root and ascending aorta has been identified in several young adult patients representing a new feature of SBP2 deficiency.Histology of aortic tissues revealed the loss of elastic and muscle fibers associated with collagen and fibrotic tissues infiltrations in the aortic wall similar to that found in Marfan, Loeys-Dietz or Ehlers-Danlos syndromes.Since murine SBP2 knockout is embryonic lethal, we used zebrafish sbp2-mutants (p.Q333X) to gain insights into human SBP2-pathology.By Western Blot (WB) we confirmed that the expression of the wild-type (WT) protein is strongly diminished in sbp2 -/-.The selenoprotein profiling assessed by qPCR and WB, showed a variable regulation of SPs expression.The mRNA expression of antioxidant enzymes (gpx1a, gpx2, trxr1, and mrsb1), and of other selenoproteins (seph, sepsh2, sep15, sepp, selt, sepn1) was significantly reduced in sbp2 -/-embryos.At protein level, we confirmed diminished expression of spsh2, sep15, selh, and selt.The thyroid function test performed by IHC and ELISA assays documented a high T4/reduced T3 levels in sbp2 -/-larvae, as a result of a reduced dio2 activity.Moreover, consistent with the low levels of antioxidant selenoenzymes, both gpx and trxr activities in sbp2 -/-were significantly lower than both sbp2 +/-and sbp2 +/+ adults at 2 and 3 months of age.The reduced antioxidant ability of mutants resulted in accumulation of reactive oxygen species (ROS) and lipid peroxide radicals (LPR), and tissue oxidative damage due to the activation of apoptosis.In particular, the analysis of the aortic tissue of sbp2 -/-adults exhibited a dilatation of the outflow tract, and a reduced expression of markers of both elastic and muscular compartments.In conclusion, zebrafish sbp2-mutants present impaired T4 to T3 conversion, antioxidant selenoenzymes deficiencies, oxidative damage and aortopathy, representing a new in vivo model that recapitulates key phenotypes of human SBP2 deficiency, enabling their pathogenesis to be further elucidated.
Source: European Thyroid Journal
DOI: 10.1159/000501012
Institution: Aalborg University
Language: English
Subfield: Nutrition and Dietetics
Field: Nursing
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4288864335