Mutation in
            <i>POLR3K</i>
            causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation

Dorboz, Imen; Dumay‐Odelot, Hélène; Boussaid, K.; Bouyacoub, Yosra; Barreau, Pauline; Samaan, Simon; Jmel, Haifa; Eymard-Pierre, Éléonore; Cancés, Claude; Bar, Céline; Poulat, Anne-Lise; Rousselle, Christophe; Renaldo, Florence; Bergès, Monique Elmaleh; Teichmann, Martin; Boespflug‐Tanguy, Odile

doi:10.1212/nxg.0000000000000289

Cited by 60 publications

(67 citation statements)

References 23 publications

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“…6,[9][10][11][12][13] It was also recently associated with a homozygous pathogenic variant in POLR3K. 14 In 2015, variants in POLR1C, encoding a common POLR1 and POLR3 subunit, were identified in 8 patients with POLR3-HLD. 15 Pathogenic variants in POLR1C were previously associated with autosomal recessive Treacher Collins syndrome (TCS), a congenital disorder of craniofacial development, in 3 unrelated patients.…”

Section: Resultsmentioning

confidence: 99%

Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants

Gauquelin

Cayami²,

Sztriha³

et al. 2019

Neurol Genet

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ObjectiveTo determine the clinical, radiologic, and molecular characteristics of RNA polymerase III-related leukodystrophy (POLR3-HLD) caused by biallelic POLR1C pathogenic variants.MethodsA cross-sectional observational study involving 25 centers worldwide was conducted. Clinical and molecular information was collected on 23 unreported and previously reported patients with POLR3-HLD and biallelic pathogenic variants in POLR1C. Brain MRI studies were reviewed.ResultsFourteen female and 9 male patients aged 7 days to 23 years were included in the study. Most participants presented early in life (birth to 6 years), and motor deterioration was seen during childhood. A notable proportion of patients required a wheelchair before adolescence, suggesting a more severe phenotype than previously described in POLR3-HLD. Dental, ocular, and endocrine features were not invariably present (70%, 50%, and 50%, respectively). Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including 1 individual with clear Treacher Collins syndrome (TCS) features. Brain MRI revealed hypomyelination in all cases, often with areas of pronounced T2 hyperintensity corresponding to T1 hypointensity of the white matter. Twenty-nine different pathogenic variants (including 12 new disease-causing variants) in POLR1C were identified.ConclusionsThis study provides a comprehensive description of POLR3-HLD caused by biallelic POLR1C pathogenic variants based on the largest cohort of patients to date. These results suggest distinct characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.

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Section: Resultsmentioning

confidence: 99%

Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants

Gauquelin

Cayami²,

Sztriha³

et al. 2019

Neurol Genet

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“…These three diseases are summarized under the name POLR3-related leukodystrophy. 51 Recently, two individuals with HLD were reported to harbor mutations in POLR3K, 52 thereby expanding the list of potential genetic defects underlying POLR3-related leukodystrophy. In addition to hypomyelination on brain imaging, the clinical phenotype of POLR3-related leukodystrophy is characterized by progressive cerebellar dysfunction and cognitive dysfunction.…”

Section: Discussionmentioning

confidence: 99%

De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia

Haijes

Koster

Rehmann

et al. 2019

The American Journal of Human Genetics

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The RNA polymerase II complex (pol II) is responsible for transcription of all $21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly diseasecausing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.

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“…Primary WRS fibroblasts also have an increase in the number and total area of nucleoli, most probably related to a direct impact of POLR3 alteration upon nucleolar function. Supporting these observations, POLR3A-related Leukodystrophies showed abnormal ribosome regulation and reduction in protein synthesis, which are important hallmarks of nucleolar dysfunction (Dorboz et al, 2018;Tetreault et al, 2011). In a recent report, the expression of the CBX4 protein, part of the polycomb repressive complex, was found reduced during senescence of human Mesenchymal Stem Cells (hMSC); while overexpression of CBX4 rescued the senescence phenotype of hMSC in a manner dependent on maintenance of nucleolar function (Ren et al, 2019).…”

Section: Discussionmentioning

confidence: 93%

Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch Syndrome fibroblasts

Baez

Valencia

Velasquez

et al. 2020

Preprint

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Recently, mutations in the RNA polymerase III subunit 3A (POLR3A) have been described as the cause of the neonatal progeria or Wiedemann-Rautenstrauch syndrome (WRS). POLR3A have important roles in the regulation of transcription of small RNAs, including tRNA, 5S rRNA and U6 snRNA. We aim to describe cellular and molecular features of WRS fibroblasts. Cultures of primary fibroblasts from one WRS patient [monoallelic POLR3A variant c.3772_3773delCT (p.Leu1258Glyfs*12)] and one control were grown. Mutation in POLR3A causes a decreased in the expression of POLR3A mRNA and protein and a sharp increased of mutant protein.In addition, there was an increased in its nuclear localization. These changes were associated to an increase number and area of nucleoli, a significantly larger nuclear area, and a high increased in the expression of pP53 and pH2AX. All these changes were associated to premature senescence. The present observations add to our understanding of the differences between HGPS and WRS, and opens new alternatives to study cell senesce and human aging.

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Mutation in POLR3K causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation

Cited by 60 publications

References 23 publications

Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants

Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants

De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia

Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch Syndrome fibroblasts

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