Bi-allelic variants in INTS11 are associated with a complex neurological disorder.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Tepe Burak, Macke Erica L, Niceta Marcello, Weisz Hubshman Monika, Kanca Oguz, Schultz-Rogers Laura, Zarate Yuri A, Schaefer G Bradley, Granadillo De Luque Jorge Luis, Wegner Daniel J, Cogne Benjamin, Gilbert-Dussardier Brigitte, Le Guillou Xavier, Wagner Eric J, Pais Lynn S, Neil Jennifer E, Mochida Ganeshwaran H, Walsh Christopher A, Magal Nurit, Drasinover Valerie, Shohat Mordechai, Schwab Tanya, Schmitz Chris, Clark Karl, Fine Anthony, Lanpher Brendan, Gavrilova Ralitza, Blanc Pierre, Burglen Lydie, Afenjar Alexandra, Steel Dora, Kurian Manju A, Prabhakar Prab, Gößwein Sophie, Di Donato Nataliya, Bertini Enrico S, Undiagnosed Diseases Network, Wangler Michael F, Yamamoto Shinya, Tartaglia Marco, Klee Eric W, Bellen Hugo J
Аннотация
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.