De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy

Djurdja Djordjevic, Maxime Pinard, Marie Soleil Gauthier, Constance Smith-Hicks, Trevor L. Hoffman, Nicole I. Wolf, Renske Oegema, Ellen van Binsbergen, Berivan Baskin, Geneviève Bernard, Sébastien Fribourg, Benoit Coulombe, Grace Yoon

Research output: Contribution to journalArticlepeer-review


POLR3B encodes the second-largest catalytic subunit of RNA polymerase III, an enzyme involved in transcription. Bi-allelic pathogenic variants in POLR3B are a well-established cause of hypomyelinating leukodystrophy. We describe six unrelated individuals with de novo missense variants in POLR3B and a clinical presentation substantially different from POLR3-related leukodystrophy. These individuals had afferent ataxia, spasticity, variable intellectual disability and epilepsy, and predominantly demyelinating sensory motor peripheral neuropathy. Protein modeling and proteomic analysis revealed a distinct mechanism of pathogenicity; the de novo POLR3B variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability. We expand the spectrum of disorders associated with pathogenic variants in POLR3B to include a de novo heterozygous POLR3B-related disorder.

Original languageEnglish (US)
Pages (from-to)186-193
Number of pages8
JournalAmerican journal of human genetics
Issue number1
StatePublished - Jan 7 2021


  • POLR3B
  • RNA polymerase III assembly
  • ataxia
  • intellectual disability
  • neuropathy
  • spasticity

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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