title: Selenoprotein-related disease in a young girl caused by nonsense mutations in the SBP2 gene.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Pediatrics, Faculty of Medicine, University Hospital of Brasília, Faculty of Health Sciences, University of Brasília, SGAN Quadra 605, Asa Norte, Prédio Novo de Ambulatórios, 70840-901, Brasília-DF, Brazil. monalisa@unb.br
authors.forename: Monalisa Ferreira
authors.initials: MF
authors.lastname: Azevedo
authors.forename: Gustavo Barcelos
authors.initials: GB
authors.lastname: Barra
authors.forename: Luciana Ansaneli
authors.initials: LA
authors.lastname: Naves
authors.forename: Lara Franciele
authors.initials: LF
authors.lastname: Ribeiro Velasco
authors.forename: Patrícia
authors.initials: P
authors.lastname: Godoy Garcia Castro
authors.forename: Luiz Claudio Gonçalves
authors.initials: LC
authors.lastname: de Castro
authors.forename: Angélica Amorim
authors.initials: AA
authors.lastname: Amato
authors.forename: Angela
authors.initials: A
authors.lastname: Miniard
authors.forename: Donna
authors.initials: D
authors.lastname: Driscoll
authors.forename: Lutz
authors.initials: L
authors.lastname: Schomburg
authors.forename: Francisco
authors.initials: F
authors.lastname: de Assis Rocha Neves
mesh_terms: D002648:Child; D018389:Codon, Nonsense; D005260:Female; D005820:Genetic Testing; D005979:Glutathione Peroxidase / Q000097:blood; D006801:Humans; D009154:Mutation; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D012643:Selenium / Q000097:blood; D051149:Selenoprotein P / Q000097:blood; D013963:Thyroid Hormones / Q000378:metabolism*
chemical_list: D018389:Codon, Nonsense; D016601:RNA-Binding Proteins; C121530:SECISBP2 protein, human; D051149:Selenoprotein P; D013963:Thyroid Hormones; D005979:Glutathione Peroxidase; D012643:Selenium