Mutations of POLR3A Encoding a Catalytic Subunit of RNA Polymerase Pol III Cause a Recessive Hypomyelinating Leukodystrophy

Abstract

Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterized by abnormal white matter visible by brain imaging. It is estimated that at least 30% to 40% of individuals remain without a precise diagnosis despite extensive investigations. We mapped tremor-ataxia with central hypomyelination (TACH) to 10q22.3-23.1 in French-Canadian families and sequenced candidate genes within this interval. Two missense and one insertion mutations in five individuals with TACH were uncovered in POLR3A, which codes for the largest subunit of RNA polymerase III (Pol III). Because these families were mapped to the same locus as leukodystrophy with oligodontia (LO) and presented clinical and radiological overlap with individuals with hypomyelination, hypodontia and hypogonadotropic hypogonadism (4H) syndrome, we sequenced this gene in nine individuals with 4H and eight with LO. In total, 14 recessive mutations were found in 19 individuals with TACH, 4H, or LO, establishing that these leukodystrophies are allelic. No individual was found to carry two nonsense mutations. Immunoblots on 4H fibroblasts and on the autopsied brain of an individual diagnosed with 4H documented a significant decrease in POLR3A levels, and there was a more significant decrease in the cerebral white matter compared to that in the cortex. Pol III has a wide set of target RNA transcripts, including all nuclear-coded tRNA. We hypothesize that the decrease in POLR3A leads to dysregulation of the expression of certain Pol III targets and thereby perturbs cytoplasmic protein synthesis. This type of broad alteration in protein synthesis is predicted to occur in other leukoencephalopathies such as hypomyelinating leukodystrophy-3, caused by mutations in aminoacyl-tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1).

RNA polymerase III component Rpc9 regulates hematopoietic stem and progenitor cell maintenance in zebrafish

“…Accordingly, the specific expression of rpc9 in the CHT region may indicate that the rapidly expanding HSPCs require many more Pol III transcripts. In fact, in the absence of Pol III components, recent reports demonstrated neuron-specific dysfunction in humans (Bernard et al, 2011;Saitsu et al, 2011;Wong et al, 2011) and digestive organ-specific defects in zebrafish (Yee et al, 2007). Intriguingly, the rpc9 heterozygous mutant embryos have no hematopoietic defects and can develop into fertile adults, similar to rpl11 (encoding ribosome protein Rpl11), nop10 (18S RNA processing) and kri1l (18S RNA maturation) mutants in zebrafish.…”

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

“…Lysates from all patients examined were strongly impaired in their ability to convert AT-rich DNA to immune-stimulatory RNA, whereas transcription of 5S rRNA was largely unaffected. Previous studies have identified mutations in POLR3A and POLR3B in patients with autosomal recessive 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy, which is a disease characterized by degeneration of the white matter in the brain (38)(39)(40). However, the functional impact of the POLR3 gene mutations in the 4H leukodystrophy patients on POL III activity remains to be established.…”

Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations

“…3 Several years later, tremor-ataxia with central hypomyelination (TACH) was described in French Canadian patients 4 and mapped to 10q22.3-10q23.31 with subsequent identification of the responsible gene, POLR3A, coding for the largest subunit of RNA polymerase III. 5 Mutations in POLR3A and POLR3B, encoding another subunit of this polymerase, were then shown to also cause 4H, as well as 2 other entities: "hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum," and "leukodystrophy with oligodontia." [6][7][8] The name Pol IIIrelated leukodystrophies has been suggested in order to include all the variations described above.…”