title: Transcriptome-wide effects of a POLR3A gene mutation in patients with an unusual phenotype of striatal involvement.
abstract: RNA polymerase III is essential for the transcription of non-coding RNAs, including tRNAs. Mutations in the genes encoding its largest subunits are known to cause hypomyelinating leukodystrophies (HLD7) with pathogenetic mechanisms hypothesised to involve impaired availability of tRNAs. We have identified a founder mutation in the POLR3A gene that leads to aberrant splicing, a premature termination codon and partial deficiency of the canonical full-length transcript. Our clinical and imaging data showed no evidence of the previously reported white matter or cerebellar involvement; instead the affected brain structures included the striatum and red nuclei with the ensuing clinical manifestations. Our transcriptome-wide investigations revealed an overall decrease in the levels of Pol III-transcribed tRNAs and an imbalance in the levels of regulatory ncRNAs such as small nuclear and nucleolar RNAs (snRNAs and snoRNAs). In addition, the Pol III mutation was found to exert complex downstream effects on the Pol II transcriptome, affecting the general regulation of RNA metabolism.
authors: Harry Perkins Institute of Medical Research and Centre for Medical Research, Level 7, QQ Block, QEII Medical Centre, 6 Verdun Street, and School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.|Department of Diagnostic Genomics, PathWest, Perth, WA 6009, Australia.
authors: Dimitar N
authors: DN
authors: Azmanov
authors: Harry Perkins Institute of Medical Research and Centre for Medical Research, Level 7, QQ Block, QEII Medical Centre, 6 Verdun Street, and School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
authors: Stefan J
authors: SJ
authors: Siira
authors: Faculty of Medicine, Department of Neurology, University Hospital Alexandrovska, Sofia Medical University, Sofia, Bulgaria.
authors: Teodora
authors: T
authors: Chamova
authors: Department of Neurology, Medical University, Varna, Bulgaria.
authors: Ara
authors: A
authors: Kaprelyan
authors: Faculty of Medicine, Department of Neurology, University Hospital Alexandrovska, Sofia Medical University, Sofia, Bulgaria.
authors: Velina
authors: V
authors: Guergueltcheva
authors: Harry Perkins Institute of Medical Research and Centre for Medical Research, Level 7, QQ Block, QEII Medical Centre, 6 Verdun Street, and School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
authors: Anne-Marie J
authors: AJ
authors: Shearwood
authors: Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA 02139, USA.
authors: Ganqiang
authors: G
authors: Liu
authors: Harry Perkins Institute of Medical Research and Centre for Medical Research, Level 7, QQ Block, QEII Medical Centre, 6 Verdun Street, and School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
authors: Bharti
authors: B
authors: Morar
authors: Harry Perkins Institute of Medical Research and Centre for Medical Research, Level 7, QQ Block, QEII Medical Centre, 6 Verdun Street, and School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
authors: Oliver
authors: O
authors: Rackham
authors: Department of Surgery and School of Medicine, The University of Western Australia, Sir Charles Gairdner Hospital, Neurological Intervention and Imaging Service of WA, Perth, WA, Australia.
authors: Michael
authors: M
authors: Bynevelt
authors: Department of Neurology, Medical University, Varna, Bulgaria.
authors: Margarita
authors: M
authors: Grudkova
authors: Faculty of Medicine, Department of Internal Medicine, Endocrinology Clinic, University Hospital Alexandrovska, Sofia Medical University, Sofia, Bulgaria.
authors: Zdravko
authors: Z
authors: Kamenov
authors: Faculty of Dental Medicine, Department of Oral and Maxillofacial Surgery, Sofia Medical University, Sofia, Bulgaria.
authors: Vassil
authors: V
authors: Svechtarov
authors: Faculty of Medicine, Department of Neurology, University Hospital Alexandrovska, Sofia Medical University, Sofia, Bulgaria.|Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria.
authors: Ivailo
authors: I
authors: Tournev
authors: Harry Perkins Institute of Medical Research and Centre for Medical Research, Level 7, QQ Block, QEII Medical Centre, 6 Verdun Street, and School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
authors: Luba
authors: L
authors: Kalaydjieva
authors: Harry Perkins Institute of Medical Research and Centre for Medical Research, Level 7, QQ Block, QEII Medical Centre, 6 Verdun Street, and School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia, aleksandra.filipovska@uwa.edu.au.
authors: Aleksandra
authors: A
authors: Filipovska
mesh_terms: D000328:Adult; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002648:Child; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D012320:RNA Polymerase III / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics; D012343:RNA, Transfer / Q000235:genetics; D014158:Transcription, Genetic; D059467:Transcriptome / Q000235:genetics*
chemical_list: D012343:RNA, Transfer; C585825:POLR3A protein, human; D012320:RNA Polymerase III