Mutations in SECISBP2 result in abnormal thyroid hormone metabolism

Abstract

Incorporation of selenocysteine (Sec), through recoding of the UGA stop codon, creates a unique class of proteins. Mice lacking tRNA(Sec) die in utero, but the in vivo role of other components involved in selenoprotein synthesis is unknown, and Sec incorporation defects have not been described in humans. Deiodinases (DIOs) are selenoproteins involved in thyroid hormone metabolism. We identified three of seven siblings with clinical evidence of abnormal thyroid hormone metabolism. Their fibroblasts showed decreased DIO2 enzymatic activity not linked to the DIO2 locus. Systematic linkage analysis of genes involved in DIO2 synthesis and degradation led to the identification of an inherited Sec incorporation defect, caused by a homozygous missense mutation in SECISBP2 (also called SBP2). An unrelated child with a similar phenotype was compound heterozygous with respect to mutations in SECISBP2. Because SBP2 is epistatic to selenoprotein synthesis, these defects had a generalized effect on selenoproteins. Incomplete loss of SBP2 function probably causes the mild phenotype.

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…Failure of this mechanism can result in miscoding of the UGA codon to be read as a stop codon resulting in an untruncated inactive deiodinase protein. The important role of deiodinases in thyroid economy has been recently emphasized by the discovery of several families with a genetic mutation in SBP2 that is either homozygous or compound heterozygous (114)(115)(116). Patients harboring these mutations present an abnormal thyroid profile characterized by low T3, high T4 and high rT3 concentrations and high normal TSH in serum.…”

Syndromes of Reduced Sensitivity to Thyroid Hormone

“…Although a total of 8 families have been identified over the period of 6 years [8,[110][111][112][113] [Dumitrescu, A.M. and Refetoff, S, unpublished data], failure of detection is likely due to the relatively mild clinical symptoms in some subjects. The inheritance is autosomal recessive and males and females are equally affected.…”

New insights into the physiological actions of selenoproteins from genetically modified mice

“…Recently, however, patients have been identified with mutations in SECIS-binding protein 2 (SBP2), an essential co-factor for translation of UGA as a Sec codon. Selenoprotein expression, including Dio2, was generally reduced in these patients leading to aberrant thyroid hormone levels and a partly insensitive thyroid hormone feedback regulatory system (41). It is very surprising that especially in light of the animal models mentioned, a general reduction of selenoprotein synthesis via reduced translational capacity becomes clinically evident as an endocrine condition.…”