Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation

Karine Choquet, Sharon Yang, Robyn D. Moir, Diane Forget, Roxanne Larivière, Annie Bouchard, Christian Poitras, Nicolas Sgarioto, Marie Josée Dicaire, Forough Noohi, Timothy E. Kennedy, Joseph Rochford, Geneviève Bernard, Martin Teichmann, Benoit Coulombe, Ian M. Willis, Claudia L. Kleinman, Bernard Brais

Research output: Contribution to journalArticle

Abstract

Recessive mutations in the ubiquitously expressed POLR3A gene cause one of the most frequent forms of childhood-onset hypomyelinating leukodystrophy (HLD): POLR3-HLD. POLR3A encodes the largest subunit of RNA Polymerase III (Pol III), which is responsible for the transcription of transfer RNAs (tRNAs) and a large array of other small non-coding RNAs. In order to study the central nervous system pathophysiology of the disease, we introduced the French Canadian founder Polr3a mutation c.2015G > A (p.G672E) in mice, generating homozygous knock-in (KI/KI) as well as compound heterozygous mice for one Polr3a KI and one null allele (KI/KO). Both KI/KI and KI/KO mice are viable and are able to reproduce. To establish if they manifest a motor phenotype, WT, KI/KI and KI/KO mice were submitted to a battery of behavioral tests over one year. The KI/KI and KI/KO mice have overall normal balance, muscle strength and general locomotion. Cerebral and cerebellar Luxol Fast Blue staining and measurement of levels of myelin proteins showed no significant differences between the three groups, suggesting that myelination is not overtly impaired in Polr3a KI/KI and KI/KO mice. Finally, expression levels of several Pol III transcripts in the brain showed no statistically significant differences. We conclude that the first transgenic mice with a leukodystrophy-causing Polr3a mutation do not recapitulate the childhood-onset HLD observed in the majority of human patients with POLR3A mutations, and provide essential information to guide selection of Polr3a mutations for developing future mouse models of the disease.

Original languageEnglish (US)
Article number13
JournalMolecular Brain
Volume10
Issue number1
DOIs
StatePublished - Apr 13 2017

Fingerprint

Mutation
RNA Polymerase III
Myelin Proteins
Small Untranslated RNA
Central Nervous System Diseases
Muscle Strength
Locomotion
Transfer RNA
Transgenic Mice
Alleles
Staining and Labeling
Phenotype
Brain
Genes

Keywords

  • Hypomyelination
  • Leukodystrophy
  • Mouse model
  • POLR3A
  • RNA Polymerase III
  • Transfer RNAs

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation. / Choquet, Karine; Yang, Sharon; Moir, Robyn D.; Forget, Diane; Larivière, Roxanne; Bouchard, Annie; Poitras, Christian; Sgarioto, Nicolas; Dicaire, Marie Josée; Noohi, Forough; Kennedy, Timothy E.; Rochford, Joseph; Bernard, Geneviève; Teichmann, Martin; Coulombe, Benoit; Willis, Ian M.; Kleinman, Claudia L.; Brais, Bernard.

In: Molecular Brain, Vol. 10, No. 1, 13, 13.04.2017.

Research output: Contribution to journalArticle

Choquet, K, Yang, S, Moir, RD, Forget, D, Larivière, R, Bouchard, A, Poitras, C, Sgarioto, N, Dicaire, MJ, Noohi, F, Kennedy, TE, Rochford, J, Bernard, G, Teichmann, M, Coulombe, B, Willis, IM, Kleinman, CL & Brais, B 2017, 'Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation' Molecular Brain, vol 10, no. 1, 13. DOI: 10.1186/s13041-017-0294-y

Choquet, Karine; Yang, Sharon; Moir, Robyn D.; Forget, Diane; Larivière, Roxanne; Bouchard, Annie; Poitras, Christian; Sgarioto, Nicolas; Dicaire, Marie Josée; Noohi, Forough; Kennedy, Timothy E.; Rochford, Joseph; Bernard, Geneviève; Teichmann, Martin; Coulombe, Benoit; Willis, Ian M.; Kleinman, Claudia L.; Brais, Bernard / Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation.

In: Molecular Brain, Vol. 10, No. 1, 13, 13.04.2017.

Research output: Contribution to journalArticle

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