The leukodystrophy mutation Polr3b R103H causes homozygote mouse embryonic lethality and impairs RNA polymerase III biogenesis

Karine Choquet, Maxime Pinard, Sharon Yang, Robyn D. Moir, Christian Poitras, Marie Josée Dicaire, Nicolas Sgarioto, Roxanne Larivière, Claudia L. Kleinman, Ian M. Willis, Marie Soleil Gauthier, Benoit Coulombe, Bernard Brais

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Recessive mutations in the ubiquitously expressed POLR3A and POLR3B genes are the most common cause of POLR3-related hypomyelinating leukodystrophy (POLR3-HLD), a rare childhood-onset disorder characterized by deficient cerebral myelin formation and cerebellar atrophy. POLR3A and POLR3B encode the two catalytic subunits of RNA Polymerase III (Pol III), which synthesizes numerous small non-coding RNAs. We recently reported that mice homozygous for the Polr3a mutation c.2015G > A (p.Gly672Glu) have no neurological abnormalities and thus do not recapitulate the human POLR3-HLD phenotype. To determine if other POLR3-HLD mutations can cause a leukodystrophy phenotype in mouse, we characterized mice carrying the Polr3b mutation c.308G > A (p.Arg103His). Surprisingly, homozygosity for this mutation was embryonically lethal with only wild-type and heterozygous animals detected at embryonic day 9.5. Using proteomics in a human cell line, we found that the POLR3B R103H mutation severely impairs assembly of the Pol III complex. We next generated Polr3a G672E/G672E /Polr3b +/R103H double mutant mice but observed that this additional mutation was insufficient to elicit a neurological or transcriptional phenotype. Taken together with our previous study on Polr3a G672E mice, our results indicate that missense mutations in Polr3a and Polr3b can variably impair mouse development and Pol III function. Developing a proper model of POLR3-HLD is crucial to gain insights into the pathophysiological mechanisms involved in this devastating neurodegenerative disease.

Original languageEnglish (US)
Article number59
JournalMolecular Brain
Issue number1
StatePublished - Jun 20 2019


  • Leukodystrophy
  • Mouse model
  • Myelination
  • POLR3A
  • POLR3B
  • RNA polymerase III

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience


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