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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 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.

Original publication

DOI

10.1016/j.ajhg.2019.06.016

Type

Journal article

Journal

American journal of human genetics

Publication Date

08/2019

Volume

105

Pages

283 - 301

Addresses

Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, the Netherlands; Department of Biomedical Genetics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, the Netherlands; German Cancer Consortium (DKTK) standort Freiburg and German Cancer Research Center (DKFZ), 79106 Heidelberg, Germany.