Selenoprotein-related disease in a young girl caused by nonsense mutations in the SBP2 gene.
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.
Azevedo
Monalisa Ferreira
MF
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
Barra
Gustavo Barcelos
GB
Naves
Luciana Ansaneli
LA
Ribeiro Velasco
Lara Franciele
LF
Godoy Garcia Castro
Patrícia
P
de Castro
Luiz Claudio Gonçalves
LC
Amato
Angélica Amorim
AA
Miniard
Angela
A
Driscoll
Donna
D
Schomburg
Lutz
L
de Assis Rocha Neves
Francisco
F
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*
D018389:Codon, Nonsense; D016601:RNA-Binding Proteins; C121530:SECISBP2 protein, human; D051149:Selenoprotein P; D013963:Thyroid Hormones; D005979:Glutathione Peroxidase; D012643:Selenium