SECISBP2 syndrome: Mouse models for an atypical form of resistance to thyroid hormone
S. Seeher1, E. Wirth1, Y. Mahdi1, A. Miniard2, D. Driscoll2, B. Carlson3, D. Hatfield3 & U. Schweizer1
An atypical form of resistance to thyroid hormone (RTH) leads to retarded growth and bone age in humans. Aberrant thyroid hormone levels (high T4, low T3, elevated rT3 and high/ normal TSH) indicate a defect in deiodinase-dependent thyroid hormone metabolism. Findings of reduced concentrations of plasma selenoproteins (SePP, GPx3) suggested a generalized defect of selenoprotein biosynthesis and led to the identification of mutations in the SECISBP2 gene. SECISBP2 is thought to play an essential role for selenoprotein biosynthesis. Mutations in the SECISBP2 gene lead to reduced expression of selenoproteins and cause a syndrome with relatively mild to more severe phenotypes. Our group set out to create mouse models to test whether Secisbp2 is essential for selenoprotein biosynthesis and to study the changes in the thyroid axis of mutant mice.
First results showed the essentiality of Secisbp2: A homozygous null mutation leads to early embryonic death. In contrast, Secisbp2 heterozygotes have no obvious phenotype. They are fertile and their thyroid function tests are normal. Biochemical examination revealed only minimal changes in selenoprotein expression. Hepatocyte-specific Secisbp2 knock-out mice appear normal too, but show a dramatic reduction of hepatic selenoprotein expression.
Neuron-specific Secisbp2 knock-out mice have a more severe phenotype. They are smaller and weight less than their wildtype littermates. Their neurological phenotype involves a movement disorder and histological stainings demonstrated a specific loss of parvalbumin positive interneurons. It will be interesting to analyze Secisbp2-mutant mice carrying point mutations found in human patients.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.