Human mutations in integrator complex subunits link transcriptome integrity to brain development

PLoS Genet. 2017 May 25;13(5):e1006809. doi: 10.1371/journal.pgen.1006809.

Renske Oegema ¹, David Baillat ², Rachel Schot ¹, Leontine M van Unen ¹, Alice Brooks ¹, Sima Kheradmand Kia ¹, A Jeannette M Hoogeboom ¹, Zheng Xia ³ ⁴, Wei Li ³ ⁴, Matteo Cesaroni ⁵, Maarten H Lequin ⁶, Marjon van Slegtenhorst ¹, William B Dobyns ⁷, Irenaeus F M de Coo ⁸, Frans W Verheijen ¹, Andreas Kremer ⁹, Peter J van der Spek ⁹, Daphne Heijsman ¹ ⁹, Eric J Wagner ², Maarten Fornerod ¹⁰, Grazia M S Mancini ¹

Affiliations

1 Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
2 Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston TX, United States of America.
3 Division of Biostatistics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States of America.
4 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States of America.
5 The Fels Institute, Temple University School of Medicine, Philadelphia, PA, United States of America.
6 Department of Pediatric Radiology, Erasmus MC- Sophia, University Medical Center Rotterdam, The Netherlands.
7 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.
8 Department of Neurology, Erasmus MC- Sophia, University Medical Center Rotterdam, The Netherlands.
9 Department of Bioinformatics, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
10 Department of Pediatric Oncology and Biochemistry, Erasmus MC, University Medical Center Rotterdam, The Netherlands.

PMID: 28542170 DOI: 10.1371/journal.pgen.1006809

Abstract

Integrator is an RNA polymerase II (RNAPII)-associated complex that was recently identified to have a broad role in both RNA processing and transcription regulation. Importantly, its role in human development and disease is so far largely unexplored. Here, we provide evidence that biallelic Integrator Complex Subunit 1 (INTS1) and Subunit 8 (INTS8) gene mutations are associated with rare recessive human neurodevelopmental syndromes. Three unrelated individuals of Dutch ancestry showed the same homozygous truncating INTS1 mutation. Three siblings harboured compound heterozygous INTS8 mutations. Shared features by these six individuals are severe neurodevelopmental delay and a distinctive appearance. The INTS8 family in addition presented with neuronal migration defects (periventricular nodular heterotopia). We show that the first INTS8 mutation, a nine base-pair deletion, leads to a protein that disrupts INT complex stability, while the second missense mutation introduces an alternative splice site leading to an unstable messenger. Cells from patients with INTS8 mutations show increased levels of unprocessed UsnRNA, compatible with the INT function in the 3'-end maturation of UsnRNA, and display significant disruptions in gene expression and RNA processing. Finally, the introduction of the INTS8 deletion mutation in P19 cells using genome editing alters gene expression throughout the course of retinoic acid-induced neural differentiation. Altogether, our results confirm the essential role of Integrator to transcriptome integrity and point to the requirement of the Integrator complex in human brain development.

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