TY - JOUR
T1 - Human mutations in integrator complex subunits link transcriptome integrity to brain development
AU - Oegema, Renske
AU - Baillat, David
AU - Schot, Rachel
AU - van Unen, Leontine M.
AU - Brooks, Alice
AU - Kia, Sima Kheradmand
AU - Hoogeboom, A. Jeannette M.
AU - Xia, Zheng
AU - Li, Wei
AU - Cesaroni, Matteo
AU - Lequin, Maarten H.
AU - van Slegtenhorst, Marjon
AU - Dobyns, William B.
AU - de Coo, Irenaeus F.M.
AU - Verheijen, Frans W.
AU - Kremer, Andreas
AU - van der Spek, Peter J.
AU - Heijsman, Daphne
AU - Wagner, Eric J.
AU - Fornerod, Maarten
AU - Mancini, Grazia M.S.
N1 - Publisher Copyright:
© 2017 Oegema et al.
PY - 2017/5
Y1 - 2017/5
N2 - 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.
AB - 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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U2 - 10.1371/journal.pgen.1006809
DO - 10.1371/journal.pgen.1006809
M3 - Article
C2 - 28542170
AN - SCOPUS:85020193310
SN - 1553-7390
VL - 13
JO - PLoS genetics
JF - PLoS genetics
IS - 5
M1 - e1006809
ER -