Bi-allelic variants in INTS11 are associated with a complex neurological disorder

Tepe, Burak; Macke, Erica L.; Niceta, Marcello; Hubshman, Monika Weisz; Kanca, Oguz; Schultz‐Rogers, Laura; Zárate, Yuri A.; Schaefer, Gerald; Luque, Jorge Luis Granadillo De; Wegner, Daniel; Cogné, Benjamin; Gilbert‐Dussardier, Brigitte; Guillou, Xavier Le; Wagner, Eric J.; Pais, Lynn; Neil, Jennifer E.; Mochida, Ganeshwaran H.; Walsh, Christopher A.; Magal, Nurit; Drasinover, Valerie; Shohat, Mordechai; Schwab, Tanya L.; Schmitz, Christopher T.; Clark, Karl J.; Fine, Anthony L.; Lanpher, Brendan C.; Gavrilova, Ralitza H.; Blanc, Pierre; Bürglen, Lydie; Afenjar, Alexandra; Steel, Dora; Kurian, Manju A.; Prabhakar, P; Gößwein, Sophie; Donato, Nataliya Di; Bertini, E.; Wangler, Michael F.; Yamamoto, Shinya; Tartaglia, Marco; Klee, Eric W.; Bellen, Hugo J.

doi:10.1016/j.ajhg.2023.03.012

Cited by 20 publications

(5 citation statements)

References 73 publications

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“…Another GO-term points to involvement in neurogenesis, which is in line with neurodevelopmental disorders connected to INT mutations. 37,43 As expected for an attenuator ∼2/3 of all DEGs (552 of 863) were upregulated upon depletion. Given that the DEGs include mRNAs of TFs (GO-term “double-stranded DNA binding”) the downregulated DEGs (311) may be due to secondary effects as suggested before.…”

Section: Resultsmentioning

confidence: 58%

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Mechanistic basis of gene-specific transcription regulation by the Integrator complex

Sabath,

Nabih,

Arnold

et al. 2024

Preprint

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The Integrator complex (INT) regulates gene expression via premature transcription termination of RNA polymerase II (RNAP2) at promoter-proximal pausing sites. This attenuation of transcription is required for cellular response to external stimuli, cell differentiation and neurodevelopment. How gene-specific regulation is achieved by INT in an inducible manner remains unclear. Here, we identify two sites on INT subunits 13/14 that serve as direct binding hubs for diverse sets of sequence-specific transcription factors (TFs) and other transcription effector complexes. The TFs co-localize with INT genome-wide, increase INT abundance on target genes and co-regulate inducible transcriptional programs. Consistently, disruption of INT-TF contacts impairs sensory cilia formation in response to glucose starvation. Structural analysis places INT's TF binding hubs upstream of the transcription bubble when attached to paused RNAP2, consistent with simultaneous TF-promoter association. Our data establish TF-mediated recruitment of INT to promoters as a widespread mechanism for targeted and inducible transcription attenuation.

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Section: Resultsmentioning

confidence: 58%

“…19,32,35–39 Consistent with a crucial function during cell differentiation and stimulus response, INTS deletions are embryonically lethal and INTS mutations cause developmental disorders, many of which manifest with neurological disease components. 37,40–43…”

Section: Introductionmentioning

confidence: 99%

Mechanistic basis of gene-specific transcription regulation by the Integrator complex

Sabath,

Nabih,

Arnold

et al. 2024

Preprint

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“…Beyond csr-1, the genome-wide RNAi screen presented in this study has also identified several yet to be characterized regulators of snRNA processing including those encoding nuclear protein complex as well as members of the endogenous siRNA pathway. Given the recent expansion of a wide-ranging role for the Integrator complex in gene expression control beyond snRNA processing, and its emerging implication in human diseases [9,15,16], it will ultimately be of interest to determine whether these novel regulators may also influence snRNA independent functions of the Integrator in contributing to transcriptome stability.…”

Section: Discussionmentioning

confidence: 99%

“…Beyond snRNA 3' processing, recent evidence has elucidated a broader role for the Integrator in contributing to transcriptional homeostasis; these functions include the 3' processing of non-coding Piwi-interacting RNAs as well as cleavage of nascent mRNAs at RNA polymerase II paused sites to facilitate either gene transcription activation or repression [12][13][14]. Phenotypically, human mutations to the Integrator complex have been linked to severe neurodevelopmental syndrome and developmental ciliopathies resulting in oral-facial digital syndromes [9,15,16]. Analysis of the Cancer Genome Atlas has also revealed an increase in non-synonymous mutations to the Integrator subunits in primary tumour samples [13,17].…”

Section: Introductionmentioning

confidence: 99%

A role for the C. elegans Argonaute protein CSR-1 in small nuclear RNA 3’ processing

Waddell,

2024

PLoS Genet

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The Integrator is a multi-subunit protein complex that catalyzes the maturation of snRNA transcripts via 3’ cleavage, a step required for snRNA incorporation with snRNP for spliceosome biogenesis. Here we developed a GFP based in vivo snRNA misprocessing reporter as a readout of Integrator function and performed a genome-wide RNAi screen for Integrator regulators. We found that loss of the Argonaute encoding csr-1 gene resulted in widespread 3’ misprocessing of snRNA transcripts that is accompanied by a significant increase in alternative splicing. Loss of the csr-1 gene down-regulates the germline expression of Integrator subunits 4 and 6 and is accompanied by a reduced protein translation efficiency of multiple Integrator catalytic and non-catalytic subunits. Through isoform and motif mutant analysis, we determined that CSR-1’s effect on snRNA processing is dependent on its catalytic slicer activity but does not involve the CSR-1a isoform. Moreover, mRNA-sequencing revealed high similarity in the transcriptome profile between csr-1 and Integrator subunit knockdown via RNAi. Together, our findings reveal CSR-1 as a new regulator of the Integrator complex and implicate a novel role of this Argonaute protein in snRNA 3’ processing.

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“…However, the study of the genotype–phenotype relationship is hampered by the limited number of affected individuals, incomplete description of clinical presentations and the heterogeneous genetic background. Variant-specific in vivo models are powerful tools for studying genotype–phenotype relationship, especially for rare diseases ( Arnadottir et al, 2017 ; Goodman et al, 2021 ; Lu et al, 2022a ; Lu et al, 2022b ; Ma et al, 2023 ; Tepe et al, 2023 ). However, systematic assessment of the effects of disease-causing variants in vivo is a challenge as it can be very labor intensive.…”

Section: Introductionmentioning

confidence: 99%

Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays

Pan,

Alvarez,

et al. 2023

eLife

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Protein UFMylation downstream of the E1 enzyme UBA5 plays essential roles in development and ER stress. Variants in the UBA5 gene are associated with developmental and epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder characterized by early-onset encephalopathy, movement abnormalities, global developmental delay, intellectual disability, and seizures. DEE44 is caused by at least twelve different missense variants described as loss of function (LoF), but the relationships between genotypes and molecular or clinical phenotypes remains to be established. We developed a humanized UBA5 fly model and biochemical activity assays in order to describe in vivo and in vitro genotype-phenotype relationships across the UBA5 allelic series. In vivo, we observed a broad spectrum of phenotypes in viability, developmental timing, lifespan, locomotor activity, and bang sensitivity. A range of functional effects was also observed in vitro across comprehensive biochemical assays for protein stability, ATP binding, UFM1 activation, and UFM1 transthiolation. Importantly, there is a strong correlation between in vivo and in vitro phenotypes, establishing a classification of LoF variants into mild, intermediate, and severe allelic strengths. By systemically evaluating UBA5 variants across in vivo and in vitro platforms, this study provides a foundation for more basic and translational UBA5 research, as well as a basis for evaluating current and future individuals afflicted with this rare disease.

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Bi-allelic variants in INTS11 are associated with a complex neurological disorder

Cited by 20 publications

References 73 publications

Mechanistic basis of gene-specific transcription regulation by the Integrator complex

Mechanistic basis of gene-specific transcription regulation by the Integrator complex

A role for the C. elegans Argonaute protein CSR-1 in small nuclear RNA 3’ processing

Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays

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