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Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.


ABSTRACT: N6-threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (t6A) is a universal modification essential for translational accuracy and efficiency. The t6A pathway uses two sequentially acting enzymes, YRDC and OSGEP, the latter being a subunit of the multiprotein KEOPS complex. We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Here we show that mutations in YRDC cause an extremely severe form of GAMOS whereas mutations in GON7, encoding the fifth KEOPS subunit, lead to a milder form of the disease. The crystal structure of the GON7/LAGE3/OSGEP subcomplex shows that the intrinsically disordered GON7 protein becomes partially structured upon binding to LAGE3. The structure and cellular characterization of GON7 suggest its involvement in the cellular stability and quaternary arrangement of the KEOPS complex.

SUBMITTER: Arrondel C 

PROVIDER: S-EPMC6722078 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Defects in t<sup>6</sup>A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.

Arrondel Christelle C   Missoury Sophia S   Snoek Rozemarijn R   Patat Julie J   Menara Giulia G   Collinet Bruno B   Liger Dominique D   Durand Dominique D   Gribouval Olivier O   Boyer Olivia O   Buscara Laurine L   Martin Gaëlle G   Machuca Eduardo E   Nevo Fabien F   Lescop Ewen E   Braun Daniela A DA   Boschat Anne-Claire AC   Sanquer Sylvia S   Guerrera Ida Chiara IC   Revy Patrick P   Parisot Mélanie M   Masson Cécile C   Boddaert Nathalie N   Charbit Marina M   Decramer Stéphane S   Novo Robert R   Macher Marie-Alice MA   Ranchin Bruno B   Bacchetta Justine J   Laurent Audrey A   Collardeau-Frachon Sophie S   van Eerde Albertien M AM   Hildebrandt Friedhelm F   Magen Daniella D   Antignac Corinne C   van Tilbeurgh Herman H   Mollet Géraldine G  

Nature communications 20190903 1


N<sup>6</sup>-threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (t<sup>6</sup>A) is a universal modification essential for translational accuracy and efficiency. The t<sup>6</sup>A pathway uses two sequentially acting enzymes, YRDC and OSGEP, the latter being a subunit of the multiprotein KEOPS complex. We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive dis  ...[more]

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