Transcriptome-wide effects of a POLR3A gene mutation in patients with an unusual phenotype of striatal involvement

Hum Mol Genet. 2016 Oct 1;25(19):4302-4314. doi: 10.1093/hmg/ddw263. Epub 2016 Aug 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Child
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology*
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Neostriatum / metabolism
  • Neostriatum / pathology
  • Nerve Degeneration / congenital*
  • Nerve Degeneration / genetics
  • Nerve Degeneration / pathology
  • Phenotype
  • RNA Polymerase III / genetics*
  • RNA Splicing / genetics
  • RNA, Transfer / genetics
  • Transcription, Genetic*
  • Transcriptome / genetics*


  • RNA, Transfer
  • POLR3A protein, human
  • RNA Polymerase III

Supplementary concepts

  • Striatal Degeneration, Autosomal Dominant