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

Arrondel, Christelle; Missoury, Sophia; Snoek, Rozemarijn; Patat, Julie; Menara, Giulia; Collinet, Bruno; Liger, Dominique; Durand, Dominique; Gribouval, Olivier; Boyer, Olivia; Buscara, Laurine; Martin, Gaëlle H.; Machuca, Eduardo; Névo, Fabien; Lescop, Ewen; Braun, Daniela A.; Boschat, Anne-Claire; Sanquer, Sylvia; Guerrera, Ida Chiara; Revy, Patrick; Parisot, Mélanie; Masson, Cécile; Boddaert, Nathalie; Charbit, Marina; Decramer, Stéphane; Novo, Robert; Macher, Marie Alice; Ranchin, Bruno; Bacchetta, Justine; Laurent, Audrey; Collardeau‐Frachon, Sophie; Eerde, Albertien M. van; Hildebrandt, Friedhelm; Magen, Daniella; Antignac, Corinne; Tilbeurgh, Herman van; Mollet, Géraldine

doi:10.1038/s41467-019-11951-x

Cited by 72 publications

(98 citation statements)

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“…In humans, pathogenic mutations have been identified in all five KEOPS genes. These mutations give rise to Galloway-Mowat syndrome (GAMOS), a severe autosomalrecessive disease that manifests in developmental defects including renal dysfunction and microcephaly, leading to early childhood mortality [8][9][10] .…”

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confidence: 99%

“…Pcc1, which binds directly to Kae1, can mediate the dimerization of KEOPS 23,24 . However, this activity of Pcc1 is not required for t 6 A catalytic activity 24 and is obstructed in eukaryotes by Gon7 binding to Pcc1 7,8,25 . Remarkably, the Kae1 orthologs in bacteria and in the mitochondria reside in protein complexes that vary considerably in size and composition from KEOPS 14 .…”

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A substrate binding model for the KEOPS tRNA modifying complex

et al. 2020

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The KEOPS complex, which is conserved across archaea and eukaryotes, is composed of four core subunits; Pcc1, Kae1, Bud32 and Cgi121. KEOPS is crucial for the fitness of all organisms examined. In humans, pathogenic mutations in KEOPS genes lead to Galloway–Mowat syndrome, an autosomal-recessive disease causing childhood lethality. Kae1 catalyzes the universal and essential tRNA modification N6-threonylcarbamoyl adenosine, but the precise roles of all other KEOPS subunits remain an enigma. Here we show using structure-guided studies that Cgi121 recruits tRNA to KEOPS by binding to its 3’ CCA tail. A composite model of KEOPS bound to tRNA reveals that all KEOPS subunits form an extended tRNA-binding surface that we have validated in vitro and in vivo to mediate the interaction with the tRNA substrate and its modification. These findings provide a framework for understanding the inner workings of KEOPS and delineate why all KEOPS subunits are essential.

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A substrate binding model for the KEOPS tRNA modifying complex

et al. 2020

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“…TsaEBD is a tRNA modification enzyme that is required for the synthesis of threonylcarbamoyl adenosine (t 6 A) (Thiaville et al, 2015;Zhang et al, 2015). t 6 A-modified tRNA is conserved in three domains of life and its deficiency sometimes causes severe dysfunctions (Thiaville et al, 2016;Arrondel et al, 2019;Ogura et al, 2019). In B. subtilis, several lines of evidence suggest a relationship between low t 6 A and protein quality control, including PDH (Ogura et al, 2019).…”

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Glucose-Mediated Protein Arginine Phosphorylation/Dephosphorylation Regulates ylxR Encoding Nucleoid-Associated Protein and Cell Growth in Bacillus subtilis

Ogura

2020

Front. Microbiol.

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Glucose is the most favorable carbon source for many bacteria, and these bacteria have several glucose-responsive networks. We proposed new glucose responsive system, which includes protein acetylation and probable translation control through TsaEBD, which is a tRNA modification enzyme required for the synthesis of threonylcarbamoyl adenosine (t 6 A)-tRNA. The system also includes nucleoid-associated protein YlxR, regulating more than 400 genes including many metabolic genes and the ylxRcontaining operon driven by the PylxS promoter is induced by glucose. Thus, transposon mutagenesis was performed for searching regulatory factors for PylxS expression. As a result, ywlE was identified. The McsB kinase phosphorylates arginine (Arg) residues of proteins and the YwlE phosphatase counteracts against McsB through Arg-dephosphorylation. Phosphorylated Arg has been known to function as a tag for ClpCP-dependent protein degradation. The previous analysis identified TsaD as an Arg-phosphorylated protein. Our results showed that the McsB/YwlE system regulates PylxS expression through ClpCP-mediated protein degradation of TsaD. In addition, we observed that glucose induced ywlE expression and repressed mcsB expression. It was concluded that these phenomena would cause glucose induction (GI) of PylxS, based on the Western blot analyses of TsaD-FLAG. These observations and the previous those that many glycolytic enzymes are Arg-phosphorylated suggested that the McsB/YwlE system might be involved in cell growth in glucose-containing medium. We observed that the disruption of mcsB and ywlE resulted in an increase of cell mass and delayed growth, respectively, in semi-synthetic medium. These results provide us broader insights to the physiological roles of the McsB/YwlE system and protein Arg-phosphorylation.

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“… 4 , 5 Over the past years, 63 genes have been identified as causing monogenic forms of SRNS (recessive or dominant) in humans with an onset <25 years. 6 , 7 , 8 , 9 Characterization of the cellular function of these 63 genes helped delineate 12 distinct pathogenic pathways of SRNS/FSGS. 6 , 7 , 8 , 9 , 10 , 11 As these genes are mainly expressed in podocytes, gene identification has helped to reveal a central role of the podocyte in the pathogenesis of SRNS.…”

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“… 6 , 7 , 8 , 9 Characterization of the cellular function of these 63 genes helped delineate 12 distinct pathogenic pathways of SRNS/FSGS. 6 , 7 , 8 , 9 , 10 , 11 As these genes are mainly expressed in podocytes, gene identification has helped to reveal a central role of the podocyte in the pathogenesis of SRNS. 6 , 7 , 8 , 9 , 10 Monogenic causation accounts for 11.0% to 29.5% of patients with SRNS with onset before 25 years, 9 , 10 , 12 , 13 leaving up to 70% of cases in that age group genetically unsolved.…”

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Generation of Monogenic Candidate Genes for Human Nephrotic Syndrome Using 3 Independent Approaches

Klämbt

Mao

Schneider

et al. 2021

Kidney International Reports

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Introduction Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of chronic kidney disease during childhood. Identification of 63 monogenic human genes has delineated 12 distinct pathogenic pathways. Methods Here, we generated 2 independent sets of nephrotic syndrome (NS) candidate genes to augment the discovery of additional monogenic causes based on whole-exome sequencing (WES) data from 1382 families with NS. Results We first identified 63 known monogenic causes of NS in mice from public databases and scientific publications, and 12 of these genes overlapped with the 63 known human monogenic SRNS genes. Second, we used a set of 64 genes that are regulated by the transcription factor Wilms tumor 1 (WT1), which causes SRNS if mutated. Thirteen of these WT1-regulated genes overlapped with human or murine NS genes. Finally, we overlapped these lists of murine and WT1 candidate genes with our list of 120 candidate genes generated from WES in 1382 NS families, to identify novel candidate genes for monogenic human SRNS. Using this approach, we identified 7 overlapping genes, of which 3 genes were shared by all datasets, including SYNPO . We show that loss-of-function of SYNPO leads to decreased CDC42 activity and reduced podocyte migration rate, both of which are rescued by overexpression of wild-type complementary DNA (cDNA), but not by cDNA representing the patient mutation. Conclusion Thus, we identified 3 novel candidate genes for human SRNS using 3 independent, nonoverlapping hypotheses, and generated functional evidence for SYNPO as a novel potential monogenic cause of NS.

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

Cited by 72 publications

References 54 publications

A substrate binding model for the KEOPS tRNA modifying complex

A substrate binding model for the KEOPS tRNA modifying complex

Glucose-Mediated Protein Arginine Phosphorylation/Dephosphorylation Regulates ylxR Encoding Nucleoid-Associated Protein and Cell Growth in Bacillus subtilis

Generation of Monogenic Candidate Genes for Human Nephrotic Syndrome Using 3 Independent Approaches

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