Proteomics

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De novo heterozygous variants in POLR2A cause a neurodevelopmental syndrome with infantile-onset hypotonia

ABSTRACT:   ABSTRACT POLR2A encodes RPB1, the largest subunit of the RNA polymerase II (pol II) complex, which is responsible for transcription of all ~21,000 protein-encoding genes. Here we describe the first fifteen patients harboring de novo heterozygous variants in POLR2A. The majority presents with profound infantile onset hypotonia and developmental delay. Missense variants that were expected to exert only mild structural effects, lead to malfunctioning RPB1, thereby inducing a dominant negative effect on pol II function. Intriguingly, these patients presented with a severe clinical phenotype. Conversely, variants expected to result in loss-of-function, leading to reduced availability of RPB1 were better tolerated: these patients exhibited the mildest phenotypes.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hela Cell

SUBMITTER: Harmjan Vos  

LAB HEAD: P.M. van Hasselt

PROVIDER: PXD011355 | Pride | 2019-09-02

REPOSITORIES: Pride

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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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