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

TitleAbsence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation.
Publication TypeJournal Article
Year of Publication2017
AuthorsChoquet K, Yang S, Moir RD, Forget D, Larivière R, Bouchard A, Poitras C, Sgarioto N, Dicaire M-J, Noohi F, Kennedy TE, Rochford J, Bernard G, Teichmann M, Coulombe B, Willis IM, Kleinman CL, Brais B
JournalMol Brain
Volume10
Issue1
Pagination13
Date Published2017 04 13
ISSN1756-6606
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.

DOI10.1186/s13041-017-0294-y
Alternate JournalMol Brain
PubMed ID28407788
PubMed Central IDPMC5391615
Grant ListR01 GM114229 / GM / NIGMS NIH HHS / United States
R01 GM120358 / GM / NIGMS NIH HHS / United States
MOP-G-287547 / / CIHR / Canada
MOP 126141 / / CIHR / Canada