例如:"lncRNA", "apoptosis", "WRKY"

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

Mol Brain. 2017 Apr 13;10(1):13
Karine Choquet 1 , Sharon Yang 2 , Robyn D Moir 3 , Diane Forget 4 , Roxanne Larivière 2 , Annie Bouchard 4 , Christian Poitras 4 , Nicolas Sgarioto 2 , Marie-Josée Dicaire 2 , Forough Noohi 5 , Timothy E Kennedy 2 , Joseph Rochford 6 , Geneviève Bernard 7 , Martin Teichmann 8 , Benoit Coulombe 9 , Ian M Willis 3 , Claudia L Kleinman 1 , Bernard Brais 10
Karine Choquet 1 , Sharon Yang 2 , Robyn D Moir 3 , Diane Forget 4 , Roxanne Larivière 2 , Annie Bouchard 4 , Christian Poitras 4 , Nicolas Sgarioto 2 , Marie-Josée Dicaire 2 , Forough Noohi 5 , Timothy E Kennedy 2 , Joseph Rochford 6 , Geneviève Bernard 7 , Martin Teichmann 8 , Benoit Coulombe 9 , Ian M Willis 3 , Claudia L Kleinman 1 , Bernard Brais 10
+ et al

[No authors listed]

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

摘要


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 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