Selenoprotein-Related Disease in a Young Girl Caused by Nonsense Mutations in the SBP2 Gene
Abstract
CONTEXT: 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. OBJECTIVE: 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. SUBJECTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Patients with SBP2 mutations have reduced levels of most selenoproteins and a multi-symptom disorder.
“Patients with mutations in the SBP2 gene have been identified who have reduced amounts of most selenoproteins and displayed a multiple-symptom disorder [69, 70, 71, 72].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [70]
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- Authors
- Azevedo, M. F., Barra, G. B., Naves, L. A., Ribeiro Velasco, L. F., Godoy Garcia Castro, P., de Castro, L. C. G., Amato, A. A., Miniard, A., Driscoll, D., Schomburg, L., & de Assis Rocha Neves, F.
- Affiliations
- Universidade de Brasília (BR)
- Sabin Institute and Laboratory of Clinical Analysis (G.B.B., L.F.R.V., P.G.G.C.), Brasília, DF, 70390-108, Brazil;
- Department of Pediatrics (L.C.G.d.C.), Faculty of Medicine, University Hospital of Brasília, Brasília, DF, 70840-901, Brazil;
- Section of Endocrinology (M.F.A., L.A.N., A.A.A.) Faculty of Medicine, University Hospital of Brasília, Brasília, DF, 70840-901, Brazil;
- Cleveland Clinic Lerner College of Medicine (US)
- Cleveland Clinic (US)
- Charité – Universitätsmedizin Berlin (DE)
- Molecular Pharmacology Laboratory (M.F.A., A.A.A., F.d.A.R.N.), Faculty of Health Sciences, University of Brasília, Brasília, DF, 70910-900. Brazil;
- Corresponding author
- Azevedo, Monalisa Ferreira
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2010-08-01
- Volume
- 95
- Issue
- 8
- Pages
- 4066-4071
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2027239245
- Cited by
- 106
- References
- 20
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 3 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 8 · 2019: 8 · 2018: 6 · 2017: 4 · 2016: 9 · 2015: 10 · 2014: 11 · 2013: 5 · 2012: 5
- FWCI
- 7.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Organoselenium and organotellurium chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- SBP2, selenocysteine incorporation, nonsense mutation, compound heterozygosity, selenoprotein P, glutathione peroxidase, thyroid hormone metabolism, congenital myopathy, intellectual disability, selenium supplementation, selenoprotein biosynthesis
- MeSH terms
- Child, Female, Genetic Testing, Glutathione Peroxidase, Humans, Mutation, Phenotype, Selenium, Thyroid Hormones, RNA-Binding Proteins, Codon, Nonsense, Selenoprotein P
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