Inborn errors of translation reinitiation in humans with Mendelian susceptibility to mycobacterial disease

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by severe infections with weakly virulent mycobacteria in otherwise healthy patients.

All known 31 genetic etiologies are inborn errors of interferon gamma (IFN-g) immunity and collectively account for about half of the cases.

We discovered private, hemizygous, predicted loss- of-function (pLOF) mutations in the X-linked ribosome recycling and reinitiation factor MCTS1 gene in five unrelated MSMD male patients.

The connection with MSMD is surprising, because the MCTS1 protein is typically thought to be involved in housekeeping of translation machinery and translational control of gene expression.

Although the genetic evidence alone is compelling, we propose to further prove causality by discovering the molecular and cellular mechanism by which MCTS1 deficiency underlies MSMD.

This project will hence help to better understand the previously unappreciated connection between regulation of translation reinitiation and IFN-g immunity. The Casanova Group has worked on MSMD for more than 25-years and identified most inborn errors of IFN-g immunity. I have spent my PhD working on the basic molecular mechanism of MCTS1.

I am therefore a highly suitable candidate to join the Casanova group and to work on this project.