Human Genetic Disorders Resulting in Systemic Selenoprotein Deficiency.

Erik Schoenmakers,Krishna Chatterjee

doi:10.3390/ijms222312927

Abstract

Selenium, a trace element fundamental to human health, is incorporated as the amino acid selenocysteine (Sec) into more than 25 proteins, referred to as selenoproteins. Human mutations in SECISBP2, SEPSECS and TRU-TCA1-1, three genes essential in the selenocysteine incorporation pathway, affect the expression of most if not all selenoproteins. Systemic selenoprotein deficiency results in a complex, multifactorial disorder, reflecting loss of selenoprotein function in specific tissues and/or long-term impaired selenoenzyme-mediated defence against oxidative and endoplasmic reticulum stress. SEPSECS mutations are associated with a predominantly neurological phenotype with progressive cerebello-cerebral atrophy. Selenoprotein deficiency due to SECISBP2 and TRU-TCA1-1 defects are characterized by abnormal circulating thyroid hormones due to lack of Sec-containing deiodinases, low serum selenium levels (low SELENOP, GPX3), with additional features (myopathy due to low SELENON; photosensitivity, hearing loss, increased adipose mass and function due to reduced antioxidant and endoplasmic reticulum stress defence) in SECISBP2 cases. Antioxidant therapy ameliorates oxidative damage in cells and tissues of patients, but its longer term benefits remain undefined. Ongoing surveillance of patients enables ascertainment of additional phenotypes which may provide further insights into the role of selenoproteins in human biological processes.

Highlights

Dietary selenium (Se) is absorbed as inorganic Se or organic Se (e.g., Se-methionine; selenocysteine) and metabolized to hydrogen selenide (H2 Se) before incorporation into the amino acid selenocysteine (Sec) [1]
The importance of selenoproteins is illustrated by the embryonic lethal phenotype of Trsp and Secisbp2 knockout mice [7,8]
It is no surprise that mutations in key components of the Sec-insertion pathway (SEPSECS, SECISBP2, TRU-TCA1-1) result in generalized deficiency of selenoproteins associated with a complex, multisystem phenotypes

Summary

Introduction

Dietary selenium (Se) is absorbed as inorganic Se (e.g., selenate; selenite) or organic Se (e.g., Se-methionine; selenocysteine) and metabolized to hydrogen selenide (H2 Se) before incorporation into the amino acid selenocysteine (Sec) [1]. Stem-loop structure located in the 30 -UTR of all selenoprotein mRNAs and the UGA codon, interacting with trans-acting factors (SECIS binding protein 2 (SECISBP2), Sec-tRNA specific eukaryotic elongation factor (EEFSEC) and Sec-tRNA[Ser]Sec ) (Figure 1), recodes UGA as a codon mediating Sec incorporation rather than termination of protein translation [3,4,5]. Such differential preservation of selenoprotein expression is attributed to the existence of a “hierarchy of selenoprotein synthesis”, whose underlying molecular basis is unclear [3,9] With this knowledge, it is no surprise that mutations in key components of the Sec-insertion pathway (SEPSECS, SECISBP2, TRU-TCA1-1) result in generalized deficiency of selenoproteins associated with a complex, multisystem phenotypes. The importance of selenoproteins is illustrated by the embryonic lethal phenotype

SECISBP2 Mutations

TRU-TCA1-1 Mutations

Sec-tRNA

Findings

Conclusions