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

Abstract

<div><p>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 <i>Integrator Complex Subunit 1 (INTS1)</i> and <i>Subunit 8</i> (<i>INTS8)</i> gene mutations are associated with rare recessive human neurodevelopmental syndromes. Three unrelated individuals of Dutch ancestry showed the same homozygous truncating <i>INTS1</i> mutation. Three siblings harboured compound heterozygous <i>INTS8</i> mutations. Shared features by these six individuals are severe neurodevelopmental delay and a distinctive appearance. The <i>INTS8</i> family in addition presented with neuronal migration defects (periventricular nodular heterotopia). We show that the first <i>INTS8</i> 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 <i>INTS8</i> 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 <i>INTS8</i> 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.</p></div