Recessive Mutations in POLR3B, Encoding the Second Largest Subunit of Pol III, Cause a Rare Hypomyelinating Leukodystrophy

Neurogenetics of Motion Laboratory, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
The American Journal of Human Genetics (Impact Factor: 10.93). 11/2011; 89(5):652-5. DOI: 10.1016/j.ajhg.2011.10.006
Source: PubMed


Mutations in POLR3A encoding the largest subunit of RNA polymerase III (Pol III) were found to be responsible for the majority of cases presenting with three clinically overlapping hypomyelinating leukodystrophy phenotypes. We uncovered in three cases without POLR3A mutation recessive mutations in POLR3B, which codes for the second largest subunit of Pol III. Mutations in genes coding for Pol III subunits are a major cause of childhood-onset hypomyelinating leukodystrophies with prominent cerebellar dysfunction, oligodontia, and hypogonadotropic hypogonadism.

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Available from: Martine Tetreault
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    • "More recently, mutations in the catalytic Pol III subunits POLR3A and POLR3B have been identified in syndromic hypomyelinating leukodystrophies, such as hypomyelination, hypodontia , and hypogonadotropic hypogonadism (4H syndrome) (Bernard et al. 2011; Saitsu et al. 2011; Tetreault et al. 2011). POLR3A mutations lead to a decrease in POLR3A levels and are predicted to interfere with the interaction with other Pol III subunits, which in turn would perturb Pol III–mediated transcription; a similar mechanism has been postulated for POLR3B-associated leukodystrophies . "
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    ABSTRACT: RNA polymerase III (Pol III) synthesizes tRNAs and other small noncoding RNAs to regulate protein synthesis. Dysregulation of Pol III transcription has been linked to cancer, and germline mutations in genes encoding Pol III subunits or tRNA processing factors cause neurogenetic disorders in humans, such as hypomyelinating leukodystrophies and pontocerebellar hypoplasia. Here we describe an autosomal recessive disorder characterized by cerebellar hypoplasia and intellectual disability, as well as facial dysmorphic features, short stature, microcephaly, and dental anomalies. Whole-exome sequencing revealed biallelic missense alterations of BRF1 in three families. In support of the pathogenic potential of the discovered alleles, suppression or CRISPR-mediated deletion of brf1 in zebrafish embryos recapitulated key neurodevelopmental phenotypes; in vivo complementation showed all four candidate mutations to be pathogenic in an apparent isoform-specific context. BRF1 associates with BDP1 and TBP to form the transcription factor IIIB (TFIIIB), which recruits Pol III to target genes. We show that disease-causing mutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1 mutations reduce Pol III-related transcription activity in vitro. Taken together, our data show that BRF1 mutations that reduce protein activity cause neurodevelopmental anomalies, suggesting that BRF1-mediated Pol III transcription is required for normal cerebellar and cognitive development. © 2015 Borck et al.; Published by Cold Spring Harbor Laboratory Press.
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    • "Though the cerebellar abnormalities appeared more severe on MRI in patients with POLR3B mutations in this study, the patients with POLR3B mutations did not have more severe clinical examinations, including cerebellar signs, than ones with POLR3A mutations. Patients with both POLR3A and POLR3B mutations presented with intellectual disability and cerebellar signs, and some had additional clinical symptoms of hypodontia or hypogonadism, as described in the literature [2] [3] [4]. All three patients with POLR3B mutations in this study could walk without support at the age of 16– 31 years, although the two with POLR3A mutations were not independent walkers at 7 and 14 years. "
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    ABSTRACT: Background: Mutations of POLR3A and POLR3B have been reported to cause several allelic hypomyelinating disorders, including hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome). Patients and methods: To clarify the difference in MRI between the two genotypes, we reviewed MRI in three patients with POLR3B mutations, and three with POLR3A mutations. Results: Though small cerebellar hemispheres and vermis are common MRI findings with both types of mutations, MRI in patients with POLR3B mutations revealed smaller cerebellar structures, especially vermis, than those in POLR3A mutations. MRI also showed milder hypomyelination in patients with POLR3B mutations than those with POLR3A mutations, which might explain milder clinical manifestations. Conclusions: MRI findings are distinct between patients with POLR3A and 3B mutations, and can provide important clues for the diagnosis, as these patients sometimes have no clinical symptoms suggesting 4H syndrome.
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