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Mol Brain. 2017 Apr 13;10(1):13. doi: 10.1186/s13041-017-0294-y.

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

Author information

1
Montreal Neurological Institute, McGill University, 3801 University Street, room 622, Montréal, Québec, H3A 2B4, Canada.
2
Department of Human Genetics, McGill University, Montréal, Québec, Canada.
3
Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.
4
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.
5
Translational Proteomics Laboratory, Institut de recherches cliniques de Montréal (IRCM), Montréal, Québec, Canada.
6
Douglas Institute Research Center, Montréal, Québec, Canada.
7
Departments of Neurology and Neurosurgery, and Pediatrics, McGill University, Montreal, Canada.
8
Department of Medical Genetics, Montreal Children's Hospital, McGill University Health Center, Montreal, Canada.
9
Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, Canada.
10
INSERM U1212 - CNRS UMR5320, Université de Bordeaux, Bordeaux, France.
11
Département de biochimie et médecine moléculaire, Université de Montréal, Montréal, Québec, Canada.
12
Montreal Neurological Institute, McGill University, 3801 University Street, room 622, Montréal, Québec, H3A 2B4, Canada. bernard.brais@mcgill.ca.
13
Department of Human Genetics, McGill University, Montréal, Québec, Canada. bernard.brais@mcgill.ca.

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.

KEYWORDS:

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

PMID:
28407788
PMCID:
PMC5391615
DOI:
10.1186/s13041-017-0294-y
[Indexed for MEDLINE]
Free PMC Article

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