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Mol Brain. 2019 Jun 20;12(1):59. doi: 10.1186/s13041-019-0479-7.

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

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, Québec, Montréal, Canada.
3
Lady Davis Institute for Medical Research, Jewish General Hospital, Québec, Montréal, Canada.
4
Translational Proteomics Laboratory, Institut de recherches cliniques de Montréal (IRCM), Québec, Montréal, Canada.
5
Department of Biochemistry, Albert Einstein College of Medicine, New York, Bronx, USA.
6
Département de biochimie et médecine moléculaire, Université de Montréal, Québec, Montréal, Canada.
7
Montreal Neurological Institute, McGill University, 3801 University Street, room 622, Montréal, Québec, H3A 2B4, Canada. bernard.brais@mcgill.ca.
8
Department of Human Genetics, McGill University, Québec, Montréal, Canada. bernard.brais@mcgill.ca.

Abstract

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 Polr3aG672E/G672E/Polr3b+/R103Hdouble 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.

KEYWORDS:

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

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