Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.
Christelle ArrondelSophia MissouryRozemarijn SnoekJulie PatatGiulia MenaraBruno CollinetDominique LigerDominique DurandOlivier GribouvalOlivia BoyerLaurine BuscaraGaëlle MartinEduardo MachucaFabien NevoEwen LescopDaniela A BraunAnne-Claire BoschatSylvia SanquerIda Chiara GuerreraPatrick RevyMélanie ParisotCécile MassonNathalie BoddaertMarina CharbitStéphane DecramerRobert NovoMarie-Alice MacherBruno RanchinJustine BacchettaAudrey LaurentSophie Collardeau FrachonAlbertien M van EerdeFriedhelm HildebrandtDaniella MagenCorinne AntignacHerman van TilbeurghGeraldine MolletPublished in: Nature communications (2019)
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.