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

Fac Rev. 2021 Feb 5;10:12. doi: 10.12703/r/10-12. eCollection 2021.


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.

Publication types

  • Review

Grant support

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).