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Defects in a universal tRNA modification pathway are responsible for the Galloway-Mowatt syndrome

Transfer RNAs (tRNA) play a central role in the protein synthesis process. tRNAs are subject to various post-transcriptional modifications that affect their stability and fine tune their activity. t6A is one of the few universal modifications of the anti-codon stem loop, grafting a threonyl-carbamoyl group onto adenosine at position 37, next to the anticodon (t6A37).

In all living organisms, the t6A biosynthesis proceeds in two steps. In the first, the Yrdc/Sua5 enzyme synthesizes an unstable threonyl-carbamoyl intermediate using CO2, ATP and Threonine. The threonyl-carbamoyl group is subsequently transferred from TC-AMP onto A37 of tRNA. The latter reaction is carried out by multiprotein complex, called KEOPS, composed of the synthesizing enzyme OSGEP, and 3 other subunits whose role has not be clarified yet (LAGE3, TP53RK and TPRKB). Recently mutations in all KEOPS subunits were identified in patients with Galloway–Mowat syndrome (GAMOS). GAMOS is an autosomal recessive disease characterized by the combination of early on set nephrotic syndrome (SRNS) and microcephaly with brain anomalies.

A collaboration between the teams of Herman van Tilbeurgh and Géraldine Mollet & Corinne Antignac of the IMAGINE institute in Paris, GAMOS causing mutations were discovered in a new small protein, GON7.


Pedigrees of families with mutations in GON7

Affected individual are represented by black boxe. chromatograms for affected individuals reveal mutations in GON7 (boxed in red). Hom, homozygous.




Proteomic and crystallographic analysis showed that Gon7 forms the fifth subunit of the human KEOPS complex by binding to LAGE3.
3D structure of OSGEP(red)/LAGE3(blue)/GON7 KEOPS-subcomplex

3D structure of OSGEP (red)/LAGE3 (blue)/GON7 (gold) KEOPS-subcomplex




GON7, unfolded when alone in solution, acquires its structure upon contact with LAGE3. The GAMOS mutation in the Gon7 results in a decreased cellular stability of the KEOPS complex. It was further shown that mutations in the upstream YrdC enzyme cause an extremely severe form of GAMOS. We now definitely established the crucial role of the t6A modification in GAMOS pathogenesis.

Reference : Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome
Arrondel et al., Nature Communications volume 10, Article number : 3967 (2019) - DOI : [10.1038/s41467-019-11951-x]

Contact : Herman van Tilbeurgh
Bruno Collinet

par Communication - publié le