Repository landing page
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- Dataset
- Dataset
- Biochemistry
- Medicine
- Microbiology
- Genetics
- Molecular Biology
- Developmental Biology
- Cancer
- Hematology
- Biological Sciences not elsewhere classified
- alternative splice site
- INTS 8 mutations show
- truncating INTS 1 mutation
- brain development Integrator
- gene expression
- siblings harboured compound
- INTS 8 mutation
- INTS 8 mutations
- INTS 8 family
- RNA polymerase II
- subunits link transcriptome integrity
- INTS 8 deletion mutation
- role
- biallelic Integrator Complex Subunit 1
- RNAPII
- RNA processing
- P 19 cells