Mutations in humans that adversely affect the selenoprotein synthesis pathway

Human mutations have been described in three genes implicated in the selenocysteine insertion pathway (SECISBP2, TRU-TCA1-1 and SEPSECS), which result in impaired synthesis of multiple selenoproteins. Mutations in these genes result in decreased gene expression and/or generate defective protein or RNA products; however, in all cases the preservation of some residual function is presumed, since selenoprotein expression is not completely abrogated. Patients harbouring SEPSECS mutations present with progressive cerebello-cerebral atrophy as the predominant phenotype, whereas this has not been associated with SECISBP2 and TRU-TCA1-1 defects. In contrast, patients with mutations in the latter two genes manifest a multisystem disorder with a thyroid hormone biochemical signature secondary to loss of selenoprotein deiodinases, myopathic features due to SEPN1 defi-ciency and phenotypes attributable to elevated levels of reactive oxygen species as a consequence of lack of antioxidant selenoenzymes. The progressive nature of most reported phenotypes may be explained by cumulative oxidative damage over time, which may also mediate the development of additional pathologies.