Abstract: SA-PO580
Defects in All Components of the t6A Biosynthesis Pathway Lead to Galloway-Mowat Syndrome
Session Information
- Noncystic Mendelian Diseases
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Genetic Diseases of the Kidney
- 802 Non-Cystic Mendelian Diseases
Authors
- Mollet, Geraldine, Inserm UMR1163-Imagine Institute-Paris Descartes University, Paris, France
- Collinet, Bruno, Université Paris Sud CNRS UMR9198, Orsay, France
- Liger, Dominique, Université Paris Sud CNRS UMR9198, Orsay, France
- Arrondel, Christelle, Inserm UMR1163-Imagine Institute-Paris Descartes University, Paris, France
- Buscara, Laurine, Inserm UMR1163-Imagine Institute-Paris Descartes University, Paris, France
- Martin, Gaelle, Inserm UMR1163-Imagine Institute-Paris Descartes University, Paris, France
- Gribouval, Olivier, Inserm UMR1163-Imagine Institute-Paris Descartes University, Paris, France
- Boyer, Olivia, Inserm UMR1163-Imagine Institute-Paris Descartes University, Paris, France
- Braun, Daniela A., Boston Children's Hospital, Boston, Massachusetts, United States
- Boschat, Anne-Claire, Inserm U1163 Imagine Institute, Paris, France
- Sanquer, Sylvia, AP-HP, Paris, France
- Magen, Daniella, Pediatric Nephrology Institute-Rambam Health Care Campus-Technion Faculty of Medicine, Haifa, Israel
- Laurent, Audrey, Hospices Civils de Lyon-Hôpital Femme-Mère-Enfant, Bron, France
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
- Van tilbeurgh, Herman, Université Paris Sud CNRS UMR9198, Orsay, France
- Antignac, Corinne, Inserm UMR1163-Imagine Institute-Paris Descartes University, Paris, France
Background
The universal threonylcarbamoyladenosine (t6A) modification on tRNAs, essential for translation initiation and translational efficiency, is catalyzed by two enzymes, YRDC and OSGEP, the last one being part of the highly conserved multiprotein complex KEOPS composed of 5 subunits (C14ORF142, LAGE3, OSGEP, TP53RK and TPRKB). Lately, we identified mutations in all 5 subunits of KEOPS in patients with Galloway-Mowat Syndrome (GAMOS, OMIM 251300) associating steroid-resistant nephrotic syndrome with microcephaly and neurological impairment. However, the role of the newly identified C14ORF142 (C14) subunit is still unclear.
Methods
To identify new genes of GAMOS and better understand the role of C14, we performed whole exome sequencing, measured t6A modification by mass-spectrometry and performed western blot and qRT-PCR of KEOPS subunits in lymphoblastoid cell lines (LCLs) from GAMOS patients.
Results
We identified compound heterozygous missense mutations in the YRDC/Sua5 gene in one patient with an extremely severe GAMOS phenotype. Interestingly, primary fibroblasts from this patient present growth defects likely due to t6A deficiency. By contrast, we did neither observe any growth defects in C14-null fibroblasts, nor any change in the t6A level in C14-mutated LCLs. Nevertheless, we demonstrated that the absence of C14 leads to a decreased expression level of the four other KEOPS subunits, likely through the shortening of the half-life of KEOPS subunits since without any effect on mRNA levels.
Conclusion
We identified mutations in an additional gene known to be involved in the biosynthesis of the t6A modification that confirms the crucial role of this modification in the pathogenesis of GAMOS. The differences in the clinical phenotypes between YRDC and C14 patients can be explained by the different role of these proteins in t6A modification, YRDC being directly involved in its biosynthesis, whereas C14 would stabilize the KEOPS complex to modulate its function(s).
Funding
- Government Support - Non-U.S.