title: tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy.
abstract: Post-transcriptional tRNA modifications are numerous and require a large set of highly conserved enzymes in humans and other organisms. In yeast, the loss of many modifications is tolerated under unstressed conditions; one exception is the N6-threonyl-carbamoyl-adenosine (t6A) modification, loss of which causes a severe growth phenotype. Here we aimed at a molecular diagnosis in a brother and sister from a consanguineous family who presented with global developmental delay, failure to thrive and a renal defect manifesting in proteinuria and hypomagnesemia. Using exome sequencing, the patients were found to be homozygous for the c.974G>A (p.(Arg325Gln)) variant of the KAE1 gene. KAE1 is a constituent of the KEOPS complex, a five-subunit complex that catalyzes the second biosynthetic step of t6A in the cytosol. The yeast KAE1 allele carrying the equivalent mutation did not rescue the t6A deficiency of the kae1Δ yeast strain as efficiently as the WT allele; furthermore, t6A levels quantified by LC-MS/MS were lower in the kae1Δ strain which was complemented by the mutation than in the kae1Δ strain, which was complemented by the WT allele. We conclude that homozygosity for c.974G>A (p.(Arg325Gln)) in KAE1 likely exerts its pathogenic effect by perturbing t6A synthesis, thereby interfering with global protein production. This is the first report of t6A biosynthesis defect in human. KAE1 joins the growing list of cytoplasmic tRNA modification enzymes, all associated with severe neurological disorders.
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.|Pediatric Neurology Unit, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Simon
authors.initials: S
authors.lastname: Edvardson
authors.affiliation: Department of Microbiology and Cell Science, Institute for Food and Agricultural Sciences and Genetic Institute, University of Florida, Gainesville, FL, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Prunetti
authors.affiliation: Hebrew University School of Medicine, Jerusalem, Israel.
authors.forename: Aiman
authors.initials: A
authors.lastname: Arraf
authors.affiliation: Department of Microbiology and Cell Science, Institute for Food and Agricultural Sciences and Genetic Institute, University of Florida, Gainesville, FL, USA.
authors.forename: Drago
authors.initials: D
authors.lastname: Haas
authors.affiliation: Department of Microbiology and Cell Science, Institute for Food and Agricultural Sciences and Genetic Institute, University of Florida, Gainesville, FL, USA.
authors.forename: Jo Marie
authors.initials: JM
authors.lastname: Bacusmo
authors.affiliation: Center for Environmental Health Sciences, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Hu
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Asas
authors.initials: A
authors.lastname: Ta-Shma
authors.affiliation: Center for Environmental Health Sciences, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.|Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Dedon
authors.affiliation: Department of Microbiology and Cell Science, Institute for Food and Agricultural Sciences and Genetic Institute, University of Florida, Gainesville, FL, USA.
authors.forename: Valérie
authors.initials: V
authors.lastname: de Crécy-Lagard
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005260:Female; D005816:Genetic Complementation Test; D006720:Homozygote; D006801:Humans; D007674:Kidney Diseases / Q000175:diagnosis / Q000235:genetics*; D008274:Magnesium / Q000378:metabolism; D008297:Male; D008661:Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D012323:RNA Processing, Post-Transcriptional; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013577:Syndrome
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; C454201:SLC4A1 protein, human; C003268:N(6)-(N-threonylcarbonyl)adenosine; D012343:RNA, Transfer; D008274:Magnesium; D000241:Adenosine