Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism

1 Center of Excellence in Neuroscience of Université de Montréal, CRCHUM, Montreal, Quebec, Canada.
Journal of Medical Genetics (Impact Factor: 6.34). 01/2013; 50(3). DOI: 10.1136/jmedgenet-2012-101357
Source: PubMed


Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterised by abnormal central nervous system white matter. Mutations in POLR3A and POLR3B genes were recently reported to cause four clinically overlapping hypomyelinating leukodystrophy phenotypes. Our aim was to investigate the presence and frequency of POLR3A and POLR3B mutations in patients with genetically unexplained hypomyelinating leukodystrophies with typical clinical and/or radiologic features of Pol III-related leukodystrophies.

The entire coding region and the flanking exon/intron boundaries of POLR3A and/or POLR3B genes were amplified and sequenced in 14 patients.

Recessive mutations in POLR3A or POLR3B were uncovered in all 14 patients. Eight novel mutations were identified in POLR3A: six missenses, one nonsense, and one frameshift mutation. Seven patients carried compound heterozygous mutations in POLR3B, of whom six shared the common mutation in exon 15 (p.V523E). Seven novel mutations were identified in POLR3B: four missenses, two splice sites, and one intronic mutation.

To date, our group has described 37 patients, of whom 27 have mutations in POLR3A and 10 in POLR3B, respectively. Altogether, our results further support the proposal that POLR3A and POLR3B mutations are a major cause of hypomyelinating leukodystrophies and suggest that POLR3A mutations are more frequent.

Download full-text


Available from: Matthis Synofzik,
  • Source
    • "Whether other affected tissues, such as the teeth, also show specific tRNA expression patterns remains to be investigated. We note that dental anomalies such as delayed dentition, hypodontia , oligodontia, and abnormally placed or shaped teeth are part of the Pol III–related leukodystrophy syndromes 4H; ataxia, delayed dentition, and hypomyelination (ADDH); and leukodystrophy with oligodontia (LO) (Daoud et al. 2013). An alternative explanation for the tissue-restricted phenotypes engendered by BRF1 dysfunction might be a partial functional redundancy with BRF2. "
    [Show abstract] [Hide abstract]
    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.
    Genome Research 01/2015; 25(2). DOI:10.1101/gr.176925.114 · 14.63 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: PNPLA6-related disorders span a phenotypic continuum characterized by variable combinations of cerebellar ataxia, upper motor neuron involvement manifesting as spasticity and/or brisk reflexes, chorioretinal dystrophy associated with variable degrees of reduced visual function, and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics). Two common but less frequent features are peripheral neuropathy (usually of axonal type manifesting as reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting) and impaired cognitive functioning (learning disabilities in children and deficits in attention, visuospatial abilities, and recall in adults). Some of these features can occur in distinct clusters on the phenotypic continuum: Boucher-Neuhäuser syndrome (cerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism); Gordon Holmes syndrome (cerebellar ataxia, hypogonadotropic hypogonadism, and – to a variable degree – brisk reflexes); and spastic paraplegia type 39 (SPG39) (upper motor neuron involvement, peripheral neuropathy, and sometimes reduced cognitive functioning and/or cerebellar ataxia). To date findings in 17 individuals from ten index families with a molecularly confirmed PNPLA6-related disorder have been reported.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: An 18-year-old German woman presented with progressive cerebellar ataxia since early childhood, delayed cognitive development, and hypogonadotropic hypogonadism. MRI demonstrated diffuse cerebral hypomyelination, cerebellar atrophy, and thin corpus callosum; X-ray revealed persistent milk teeth and hypoplastic crowns and roots (figure), indicative of 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism). POLR3B sequencing(1) revealed 2 compound heterozygous mutations (C527R [C.1579T>C] and the common ancestral V523E [C.1568T>A](2)).
    Neurology 11/2013; 81(19):e145. DOI:10.1212/01.wnl.0000435300.64776.7e · 8.29 Impact Factor
Show more