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.
Bibliographical noteFunding Information:
Work in the Wagner laboratory is funded from the Welch Foundation (H-1889). Work in the Mancini laboratory was supported by the Erasmus MC grant (Mrace nr. 104673 to GMSM). Work in the Erasmus MC Bioinformatics department was supported by CTMM and Lygature grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank the families for the trust and collaboration throughout the years. Also we would like to thank Dr. Annemieke J. Verkerk for support during the early stages of the project and Dr. Debbie van den Berg for useful discussion on INTS1.