POLR3-related leukodystrophy: How do mutations affecting RNA polymerase III subunits cause hypomyelination?

doi:10.12703/r/10-12

Review

. 2021 Feb 5:10:12.

doi: 10.12703/r/10-12. eCollection 2021.

POLR3-related leukodystrophy: How do mutations affecting RNA polymerase III subunits cause hypomyelination?

Benoit Coulombe^{1

2}, Alexa Derksen^{1

3

4}, Roberta La Piana^{5

6}, Bernard Brais^{5

7}, Marie-Soleil Gauthier¹, Geneviève Bernard^{3

4

7

8

9}

Affiliations

¹ Department of Translational Proteomics, Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada.
² Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada.
³ Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada.
⁴ Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
⁵ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
⁶ Department of Diagnostic Radiology, McGill University, Montréal, QC, Canada.
⁷ Department of Human Genetics, McGill University, Montréal, QC, Canada.
⁸ Department of Pediatrics, McGill University, Montréal, QC, Canada.
⁹ Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Center, Montréal, QC, Canada.

PMID: 33659930
PMCID: PMC7894263
DOI: 10.12703/r/10-12

Review

POLR3-related leukodystrophy: How do mutations affecting RNA polymerase III subunits cause hypomyelination?

Benoit Coulombe et al. Fac Rev. 2021.

. 2021 Feb 5:10:12.

doi: 10.12703/r/10-12. eCollection 2021.

Authors

Benoit Coulombe^{1

2}, Alexa Derksen^{1

3

4}, Roberta La Piana^{5

6}, Bernard Brais^{5

7}, Marie-Soleil Gauthier¹, Geneviève Bernard^{3

4

7

8

9}

Affiliations

¹ Department of Translational Proteomics, Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada.
² Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada.
³ Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada.
⁴ Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
⁵ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
⁶ Department of Diagnostic Radiology, McGill University, Montréal, QC, Canada.
⁷ Department of Human Genetics, McGill University, Montréal, QC, Canada.
⁸ Department of Pediatrics, McGill University, Montréal, QC, Canada.
⁹ Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Center, Montréal, QC, Canada.

PMID: 33659930
PMCID: PMC7894263
DOI: 10.12703/r/10-12

Abstract

Hypomyelinating leukodystrophies are a group of genetic disorders characterized by insufficient myelin deposition during development. A subset of hypomyelinating leukodystrophies, named RNA polymerase III (Pol III or POLR3)-related leukodystrophy or 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) leukodystrophy, was found to be caused by biallelic variants in genes encoding subunits of the enzyme Pol III, including POLR3A, POLR3B, POLR3K, and POLR1C. Pol III is one of the three nuclear RNA polymerases that synthesizes small non-coding RNAs, such as tRNAs, 5S RNA, and others, that are involved in the regulation of essential cellular processes, including transcription, translation and RNA maturation. Affinity purification coupled with mass spectrometry (AP-MS) revealed that a number of mutations causing POLR3-related leukodystrophy impair normal assembly or biogenesis of Pol III, often causing a retention of the unassembled subunits in the cytoplasm. Even though these proteomic studies have helped to understand the molecular defects associated with leukodystrophy, how these mutations cause hypomyelination has yet to be defined. In this review we propose two main hypotheses to explain how mutations affecting Pol III subunits can cause hypomyelination.

Keywords: RNA polymerase III; genetic disease; leukodystrophy; myelination; protein complex assembly.

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Conflict of interest statement

The authors declare that they have no competing interests.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

Figures

**Figure 1.. Side view of the cryogenic electron microscopy structure of the *Saccharomyces cerevisiae* RNA polymerase III open DNA complex (Protein Data Bank code: 6EU1).**
Template and non-template strands of DNA are shown in yellow (perpendicular to the screen). Human leukodystrophy-causative subunits POLR3A, POLR3B, POLR1C, and POLR3K are labelled. POLR3G, which is homologous to POLR3GL, is also indicated. All other subunits are in gray.

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References

1. Schiffmann R, van der Knaap MS: The latest on leukodystrophies. Curr Opin Neurol. 2004; 17(2): 187–92. 10.1097/00019052-200404000-00017 - DOI - PubMed
1. Schiffmann R, van der Knaap MS: Invited article: An MRI-based approach to the diagnosis of white matter disorders. Neurology. 2009; 72(8): 750–9. 10.1212/01.wnl.0000343049.00540.c8 - DOI - PMC - PubMed
1. Bernard G, Vanderver A: POLR3-Related Leukodystrophy. In: M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. Stephens and A. Amemiya, eds. GeneReviews(®) Seattle WA: © 1993–2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle; 1993. Reference Source - PubMed
1. Bernard G, Chouery E, Putorti ML, et al. : Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet. 2011; 89(3): 415–23. 10.1016/j.ajhg.2011.07.014 - DOI - PMC - PubMed
1. Tétreault M, Choquet K, Orcesi S, et al. : Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy. Am J Hum Genet. 2011; 89(5): 652–5. 10.1016/j.ajhg.2011.10.006 - DOI - PMC - PubMed

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This study was supported by grants from the Canadian Institutes of Health Research (CIHR, 201610PJT-377869, project grant 426534). BC is the recipient of the IRCM Bell-Bombardier Research Chair. AD is supported by the CIHR Canadian Graduates Scholarships – Master’s, the Fondation du Grand Defi Pierre Lavoie Master’s Scholarship, and Heathy Brains for Healthy Lives Masters Fellowship. GB has received a Research Scholar Junior 1 award from the Fonds de Recherche du Québec – Santé (FRQS) (2012–2016) and the New Investigator Salary Award from the CIHR (2017–2022).

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[1] Schiffmann R, van der Knaap MS: The latest on leukodystrophies. Curr Opin Neurol. 2004; 17(2): 187–92. 10.1097/00019052-200404000-00017 - DOI - PubMed

[2] Schiffmann R, van der Knaap MS: The latest on leukodystrophies. Curr Opin Neurol. 2004; 17(2): 187–92. 10.1097/00019052-200404000-00017 - DOI - PubMed

[3] Schiffmann R, van der Knaap MS: Invited article: An MRI-based approach to the diagnosis of white matter disorders. Neurology. 2009; 72(8): 750–9. 10.1212/01.wnl.0000343049.00540.c8 - DOI - PMC - PubMed

[4] Schiffmann R, van der Knaap MS: Invited article: An MRI-based approach to the diagnosis of white matter disorders. Neurology. 2009; 72(8): 750–9. 10.1212/01.wnl.0000343049.00540.c8 - DOI - PMC - PubMed

[5] Bernard G, Vanderver A: POLR3-Related Leukodystrophy. In: M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. Stephens and A. Amemiya, eds. GeneReviews(®) Seattle WA: © 1993–2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle; 1993. Reference Source - PubMed

[6] Bernard G, Vanderver A: POLR3-Related Leukodystrophy. In: M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. Stephens and A. Amemiya, eds. GeneReviews(®) Seattle WA: © 1993–2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle; 1993. Reference Source - PubMed

[7] Bernard G, Chouery E, Putorti ML, et al. : Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet. 2011; 89(3): 415–23. 10.1016/j.ajhg.2011.07.014 - DOI - PMC - PubMed

[8] Bernard G, Chouery E, Putorti ML, et al. : Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet. 2011; 89(3): 415–23. 10.1016/j.ajhg.2011.07.014 - DOI - PMC - PubMed

[9] Tétreault M, Choquet K, Orcesi S, et al. : Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy. Am J Hum Genet. 2011; 89(5): 652–5. 10.1016/j.ajhg.2011.10.006 - DOI - PMC - PubMed

[10] Tétreault M, Choquet K, Orcesi S, et al. : Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy. Am J Hum Genet. 2011; 89(5): 652–5. 10.1016/j.ajhg.2011.10.006 - DOI - PMC - PubMed

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POLR3-related leukodystrophy: How do mutations affecting RNA polymerase III subunits cause hypomyelination?

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POLR3-related leukodystrophy: How do mutations affecting RNA polymerase III subunits cause hypomyelination?

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