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- Title
Transcriptome-wide effects of a POLR3A gene mutation in patients with an unusual phenotype of striatal involvement.
- Authors
Azmanov, Dimitar N.; Siira, Stefan J.; Chamova, Teodora; Kaprelyan, Ara; Guergueltcheva, Velina; Shearwood, Anne-Marie J.; Liu, Ganqiang; Morar, Bharti; Rackham, Oliver; Bynevelt, Michael; Grudkova, Margarita; Kamenov, Zdravko; Svechtarov, Vassil; Tournev, Ivailo; Kalaydjieva, Luba; Filipovska, Aleksandra
- 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 downstreameffects on the Pol II transcriptome, affecting the general regulation of RNA metabolism.
- Publication
Human Molecular Genetics, 2016, Vol 25, Issue 19, p4302
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddw263