Coulombe Benoit, Derksen Alexa, La Piana Roberta, Brais Bernard, Gauthier Marie-Soleil, Bernard Geneviève
Department of Translational Proteomics, Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada.
Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada.
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.
髓鞘形成不足性脑白质营养不良是一组遗传性疾病，其特征是在发育过程中髓鞘沉积不足。髓鞘形成不足性脑白质营养不良的一个子集，称为RNA聚合酶III（Pol III或POLR3）相关脑白质营养不良或4H（髓鞘形成不足、牙发育不全和低促性腺激素性腺功能减退）脑白质营养不良，被发现是由编码Pol III酶亚基的基因中的双等位基因变异引起的，包括POLR3A、POLR3B、POLR3K和POLR1C。Pol III是三种核RNA聚合酶之一，可合成小的非编码RNA，如tRNA、5S RNA等，这些RNA参与包括转录、翻译和RNA成熟在内的基本细胞过程的调控。亲和纯化结合质谱分析（AP-MS）表明，许多导致POLR3相关脑白质营养不良的突变会损害Pol III的正常组装或生物发生，常常导致未组装的亚基滞留在细胞质中。尽管这些蛋白质组学研究有助于理解与脑白质营养不良相关的分子缺陷，但这些突变如何导致髓鞘形成不足尚未明确。在这篇综述中，我们提出两个主要假说来解释影响Pol III亚基的突变如何导致髓鞘形成不足。
