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


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.

SUBMITTER: Haijes HA 

PROVIDER: S-EPMC6699192 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Haijes Hanneke A HA   Koster Maria J E MJE   Rehmann Holger H   Li Dong D   Hakonarson Hakon H   Cappuccio Gerarda G   Hancarova Miroslava M   Lehalle Daphne D   Reardon Willie W   Schaefer G Bradley GB   Lehman Anna A   van de Laar Ingrid M B H IMBH   Tesselaar Coranne D CD   Turner Clesson C   Goldenberg Alice A   Patrier Sophie S   Thevenon Julien J   Pinelli Michele M   Brunetti-Pierri Nicola N   Prchalová Darina D   Havlovicová Markéta M   Vlckova Markéta M   Sedláček Zdeněk Z   Lopez Elena E   Ragoussis Vassilis V   Pagnamenta Alistair T AT   Kini Usha U   Vos Harmjan R HR   van Es Robert M RM   van Schaik Richard F M A RFMA   van Essen Ton A J TAJ   Kibaek Maria M   Taylor Jenny C JC   Sullivan Jennifer J   Shashi Vandana V   Petrovski Slave S   Fagerberg Christina C   Martin Donna M DM   van Gassen Koen L I KLI   Pfundt Rolph R   Falk Marni J MJ   McCormick Elizabeth M EM   Timmers H T Marc HTM   van Hasselt Peter M PM  

American journal of human genetics 20190725 2


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  ...[more]

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