Selenoprotein-related disease in a young girl caused by nonsense mutations in the SBP2 gene
| Autor: | Patrícia Castro, Monalisa F. Azevedo, Lara Franciele Ribeiro Velasco, Gustavo Barcelos Barra, Donna M. Driscoll, Francisco de Assis Rocha Neves, Luciana Ansaneli Naves, Angélica Amorim Amato, Lutz Schomburg, Luiz Claudio Castro, Angela C. Miniard |
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| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_specialty
Thyroid Hormones Endocrinology Diabetes and Metabolism Clinical Biochemistry Nonsense mutation Biology Biochemistry chemistry.chemical_compound Selenium Endocrinology Internal medicine Selenoprotein P medicine Coding region Humans Genetic Testing Child Gene chemistry.chemical_classification Genetics Glutathione Peroxidase Selenocysteine Biochemistry (medical) RNA-Binding Proteins Heterozygote advantage medicine.disease Phenotype Congenital myopathy chemistry Codon Nonsense Mutation Female Selenoprotein |
| Zdroj: | The Journal of clinical endocrinology and metabolism. 95(8) |
| ISSN: | 1945-7197 |
| Popis: | Selenoproteins are essential for life, and their biosynthesis requires the incorporation of the rare amino acid selenocysteine (Sec) in a process mediated by the Sec insertion sequence-binding protein 2 (SBP2). Although SBP2 is considered a rate-limiting factor mediating Sec incorporation, there has been little evidence so far linking SBP2 dysfunction to widespread selenoprotein-related disease.The objective of the study was to report the discovery of novel truncation mutations in the SBP2 gene (R120X/R770X) in a female adolescent and the clinical consequences of the combined deficiency of selenoproteins.A 12-yr-old girl who presented with a syndrome of abnormal thyroid hormone metabolism, delayed bone maturation, congenital myopathy, and impaired mental and motor coordination development and her family were studied. The coding region of the SBP2 gene was analyzed by sequencing, and gel shift assays were performed to address the in vitro binding properties of the mutant SBP2 protein.Serum levels of selenium and glutathione peroxidase in the proband were reduced, and selenoprotein P levels were undetectable. DNA sequencing of the SBP2 gene revealed a compound heterozygous mutation (R120X/R770X). The R120X mutation disrupted all functional motifs and the R770X inhibited the binding of SBP2 to Sec insertion sequence elements. Interestingly, selenium supplementation normalized serum selenium and glutathione peroxidase but not selenoprotein P levels and did not restore thyroid hormone metabolism dysfunction.This distinctive phenotype can only be explained by the combined deficiency of functionally important selenoproteins and pinpoints the clinical relevance of selenoproteins and selenium economy in human development. |
| Databáze: | OpenAIRE |
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