Publication Date
5-4-2023
Journal
American Journal of Human Genetics
DOI
10.1016/j.ajhg.2023.03.012
PMID
37054711
PMCID
PMC10183469
PubMedCentral® Posted Date
4-12-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Adult, Animals, Humans, Drosophila, Drosophila Proteins, Mutation, Nervous System Diseases, RNA, Messenger, INTS11, CPSF3L, Drosophila, dIntS11, developmental delay, intellectual disability, delayed language development, impaired motor development, brain atrophy
Abstract
The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog of INTS11, dIntS11, is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. Using Drosophila as a model, we investigated the effect of seven variants. We found that two (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants, indicating that they are strong loss-of-function variants. Furthermore, we found that five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met, and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Altogether, our results provide compelling evidence that integrity of the Integrator RNA endonuclease is critical for brain development.
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