ArticleAmerican journal of human genetics2019
De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia.
Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 72 citations in OpenAlex.
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- Human FUS is toxic via association with RNA polymerase II in Drosophila.Cell death & disease · 2026Article
- Identification of a Novel Missense Homozygous Variant in LINS1 in Two Distinct Iranian Families With Consanguineous Marriage.Molecular genetics & genomic medicine · 2026Article
- Integrative transcriptomic- neuroimaging analysis reveals polygenic correlates of interhemispheric functional decoupling in ischemic stroke.Frontiers in cellular neuroscience · 2026Article
- Regulatory Effects of Endometriosis-Associated Genetic Variants: A Multi-Tissue eQTL Analysis.Diseases (Basel, Switzerland) · 2025Article
- De novo and inherited variants in DDX39B cause a novel neurodevelopmental syndrome.Brain : a journal of neurology · 2025Article
- Further delineation of the SCAF4-associated neurodevelopmental disorder.European journal of human genetics : EJHG · 2025Article
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- Strabismus in Genetic Syndromes: A Review.Clinical & experimental ophthalmology · 2025Review
- RNA Polymerase II Activity Control of Gene Expression and Involvement in Disease.Journal of molecular biology · 2025Review
- Epigenetic aging of semen is associated with inflammation.Epigenetics · 2024Article
- Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling.Molecular autism · 2024Article
- Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.Genome medicine · 2024Article
- TANGO6 regulates cell proliferation via COPI vesicle-mediated RPB2 nuclear entry.Nature communications · 2024Article
- Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.medRxiv : the preprint server for health sciences · 2024Article
- RNA Pol II Assembly Affects ncRNA Expression.International journal of molecular sciences · 2023Article
- Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases.Genome medicine · 2023Article
- Never a dull enzyme, RNA polymerase II.Transcription · 2023Review
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Authors and funding
44 authors at 20 institutions in 11 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 disease-causing. 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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