title: A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition.
abstract: Intellectual disability is a common and highly heterogeneous disorder etiologically. In a multiplex consanguineous family, we applied autozygosity mapping and exome sequencing and identified a novel homozygous truncating mutation in PUS3 that fully segregates with the intellectual disability phenotype. Consistent with the known role of Pus3 in isomerizing uracil to pseudouridine at positions 38 and 39 in tRNA, we found a significant reduction in this post-transcriptional modification of tRNA in patient cells. Our finding adds to a growing list of intellectual disability disorders that are caused by perturbation of various tRNA modifications, which highlights the sensitivity of the brain to these highly conserved processes.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.affiliation: Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Eissa
authors.initials: E
authors.lastname: Faqeih
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Nour
authors.initials: N
authors.lastname: Ewida
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Eman
authors.initials: E
authors.lastname: Alobeid
authors.affiliation: Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. eric_phizicky@urmc.rochester.edu.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Phizicky
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003071:Cognition / Q000502:physiology; D059472:Exome / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D006836:Hydro-Lyases / Q000235:genetics*; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011560:Pseudouridine / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D012343:RNA, Transfer / Q000235:genetics*
chemical_list: D011560:Pseudouridine; D012343:RNA, Transfer; D006836:Hydro-Lyases; C022479:pseudouridylate synthetase