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.
J Clin Endocrinol Metab. 2010 Aug;95(8):4066-71. doi: 10.1210/jc.2009-2611. Epub 2010 May 25.
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.
硒蛋白对生命至关重要，其生物合成需要在 Sec 插入序列结合蛋白 2（SBP2）介导的过程中将稀有氨基酸硒代半胱氨酸（Sec）掺入。尽管 SBP2 被认为是介导 Sec 掺入的限速因素，但迄今为止，将 SBP2 功能障碍与广泛的硒蛋白相关疾病联系起来的证据很少。
本研究旨在报道在一名青春期女性中发现 SBP2 基因（R120X/R770X）的新型截断突变，并报告硒蛋白联合缺乏的临床后果。
研究了一名 12 岁女孩，其表现为甲状腺激素代谢异常、骨成熟延迟、先天性肌病以及精神和运动协调发育受损的综合征，并对其家族进行了研究。通过测序分析 SBP2 基因的编码区，并进行凝胶迁移分析以解决突变 SBP2 蛋白的体外结合特性。
先证者的血清硒和谷胱甘肽过氧化物酶水平降低，而硒蛋白 P 水平无法检测到。SBP2 基因的 DNA 测序显示复合杂合突变（R120X/R770X）。R120X 突变破坏了所有功能结构域，而 R770X 抑制了 SBP2 与 Sec 插入序列元件的结合。有趣的是，硒补充剂使血清硒和谷胱甘肽过氧化物酶正常化，但不能使硒蛋白 P 水平正常化，也不能恢复甲状腺激素代谢功能障碍。
这种独特的表型只能用功能重要的硒蛋白联合缺乏来解释，并指出了硒蛋白和人类发育中硒经济的临床相关性。
