ArticleAmerican journal of human genetics2023
Bi-allelic variants in INTS11 are associated with a complex neurological disorder.
Registry-linked trialOpen access · greenAbstract read
In one paragraph
Article in American journal of human genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 23 papers.
0numbers the graph read from it
0cells of the map it votes in
23citing papers in PubMed
5.4field-weighted citation impact, top 4% of its field
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network
Who cites it
23 citing papers in PubMed, 35 citations in OpenAlex.
- Regulation of RNA transcript elongation in metazoans and its relevance to disease.Nature reviews. Molecular cell biology · 2026Review
- Expanding the Phenotypic Spectrum of INTS11-Related Neurodevelopmental Disorder.Indian journal of pediatrics · 2026Article
- Unprocessed U1 snRNAs as a biomarker of INTS11- and BRAT1-related neurodevelopmental disorders.Genome medicine · 2026Article
- Integrator subunit IntS11 orchestrates the temporal dynamics of neural lineage progression in Drosophila.Cell & bioscience · 2026Article
- Rare heterozygous de novo variants in RAPGEF2 are associated with a neurodevelopmental disorder.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Integrator 20th anniversary: a molecular machine indispensable in development and disease.Trends in molecular medicine · 2026Review
- Characterizing a Unique Retinal Phenotype in INTS11-Associated Neurodevelopmental Disorder.Investigative ophthalmology & visual science · 2026Article
- Neurotrophic Modulation Restores Motor and Developmental Defects in Zebrafish Models of ints11 Deficiency.Journal of neurochemistry · 2026Article
- Coxsackievirus B3 Cleaves INTS10 Through 3C Protease to Facilitate Its Replication.International journal of molecular sciences · 2026Article
- Integrator promotes the association of TFIID and RNA polymerase II to maintain pluripotency during development.Molecular cell · 2025Article
- Article
- Differential effect of ubiquitous and germline depletion of Integrator complex function on C. elegans physiology.Biology open · 2025Article
- De novo variants in CDKL1 and CDKL2 are associated with neurodevelopmental symptoms.American journal of human genetics · 2025Article
- Requirement of CSR-1 isoforms and catalytic activity formicroPublication biology · 2025Article
- The enhancer module of Integrator controls cell identity and early neural fate commitment.Nature cell biology · 2025Article
- INTS11-related neurodevelopmental disorder: a case report and literature review.Journal of human genetics · 2024Review
- Review
- Cytoplasmic binding partners of the Integrator endonuclease INTS11 and its paralog CPSF73 are required for their nuclear function.Molecular cell · 2024Article
- Article
- A role for the C. elegans Argonaute protein CSR-1 in small nuclear RNA 3' processing.PLoS genetics · 2024Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
42 authors at 19 institutions in 6 countries.
Burak TepeDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
Erica L MackeCenter for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Marcello NicetaMolecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Monika Weisz HubshmanDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Oguz KancaDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
Laura Schultz-RogersCenter for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Yuri A ZarateDivision of Genetics and Metabolism, University of Kentucky, Lexington, KY, USA.
G Bradley SchaeferSection of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Jorge Luis Granadillo De LuqueDivision of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
Daniel J WegnerEdward Mallinckrodt Department of Pediatrics, Washington University in St. Louis School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri, USA.
Benjamin CogneLaboratory of Molecular Genetics, CHU de Nantes, Nantes, France.
Brigitte Gilbert-DussardierDepartment of Medical Genetics, CHU de Poitiers, Poitiers, France.
Xavier Le GuillouDepartment of Medical Genetics, CHU de Poitiers, Poitiers, France.
Eric J WagnerDepartment of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester School of Medicine, Rochester, NY 14642, USA.
Lynn S PaisDivision of Genetics and Genomics, and Howard Hughes Medical Institute, Boston Children's Hospital, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jennifer E NeilDivision of Genetics and Genomics, and Howard Hughes Medical Institute, Boston Children's Hospital, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA.
Ganeshwaran H MochidaDivision of Genetics and Genomics, and Howard Hughes Medical Institute, Boston Children's Hospital, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Christopher A WalshDivision of Genetics and Genomics, and Howard Hughes Medical Institute, Boston Children's Hospital, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA.
Nurit MagalThe Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel.
Valerie DrasinoverThe Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel.
Mordechai ShohatCancer Research Center, Chaim Sheba Medical Center, Ramat Gan, Israel; Medical Genetics Institute of Maccabi HMO, Rechovot, Israel.
Tanya SchwabCenter for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Chris SchmitzCenter for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Karl ClarkCenter for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Anthony FineDepartment of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
Brendan LanpherDepartment of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
Ralitza GavrilovaDepartment of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
Pierre BlancAPHP, Département de génétique, Sorbonne Université, GRC n°19, ConCer-LD, Centre de Référence déficiences intellectuelles de causes rares, Hôpital Armand Trousseau, 75012 Paris, France.
Lydie BurglenAPHP, Département de génétique, Sorbonne Université, GRC n°19, ConCer-LD, Centre de Référence déficiences intellectuelles de causes rares, Hôpital Armand Trousseau, 75012 Paris, France.
Alexandra AfenjarAPHP. SU, Centre de Référence Malformations et maladies congénitales du cervelet, département de génétique et embryologie médicale, Hôpital Trousseau, 75012 Paris, France.
Dora SteelDevelopmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, UK; Department of Neurology, Great Ormond Street Hospital for Children, London, UK.
Manju A KurianDevelopmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, UK; Department of Neurology, Great Ormond Street Hospital for Children, London, UK.
Prab PrabhakarDepartment of Neurology, Great Ormond Street Hospital for Children, London, UK.
Sophie GößweinInstitute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
Nataliya Di DonatoInstitute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
Enrico S BertiniUnit of Neuromuscular and Neurodegenerative Disorders, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Undiagnosed Diseases Network
Michael F WanglerDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
Shinya YamamotoDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Marco TartagliaMolecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Eric W KleeCenter for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
Hugo J BellenDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hbellen@bcm.edu.
Baylor College of Medicine · USMayo Clinic · USBoston Children's Hospital · USGreat Ormond Street Hospital · GBSt. Louis Children's Hospital · USBambino Gesù Children's Hospital · ITMayo Clinic in Florida · USUniversity Hospital Carl Gustav Carus · DECentre Hospitalier Universitaire de Nantes · FRCentre Hospitalier Universitaire de Poitiers · FRRafael Advanced Defense Systems (Israel) · ILSorbonne Université · FRAssistance Publique – Hôpitaux de Paris · FRBroad Institute · USSheba Medical Center · ILUniversity of Arkansas for Medical Sciences · USUniversity of Kentucky · USUniversity of Rochester · USWashington University in St. Louis · US
Funding
UNDERSTANDING FXTAS AMONG MALES WITH THE FMR1 PREMUTATIONP30HD024064 · NICHD · BAYLOR COLLEGE OF MEDICINE · PI ROSENMUND, CHRISTIAN · 1988 to 2013
$29.4MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MPreclinical and Clincial OutcomesP50HD103555 · NICHD · BAYLOR COLLEGE OF MEDICINE · PI Sandesh Chakravarthy Sreenath Nagamani, David Loren Nelson · 2020 to 2026
$9.9MHUMAN EPILEPSY GENETICS--NEURONAL MIGRATION DISORDERSR01NS035129 · NINDS · BOSTON CHILDREN'S HOSPITAL · PI WALSH, CHRISTOPHER A. · 1997 to 2023
$9.5MGenetic Analysis and Manipulation Core (GAEC)P50HD105351 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI Hisashi Umemori · 2021 to 2026
$9.4MZebrafish CoreU54NS093793 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI BELLEN, HUGO J · 2015 to 2022
$7.5MExpansion and characterization of the Drosophila Toolkit to study SARS-CoV-2R24OD022005 · OD · BAYLOR COLLEGE OF MEDICINE · PI BELLEN, HUGO J · 2016 to 2023
$7.4MA Comprehensive Resource for Manipulating the Drosophila GenomeR24OD031447 · OD · BAYLOR COLLEGE OF MEDICINE · PI HUGO J BELLEN, Oguz Kanca · 2021 to 2026
$5.2MProbing the specificity and activity of the metazoan Integrator complexR01GM134539 · NIGMS · HARVARD MEDICAL SCHOOL · PI Karen L Adelman, ERIC J WAGNER · 2019 to 2026
$4.7MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MIMPACTS OF GLIAL LIPID DROPLETS ON OXIDATIVE STRESS AND NEURODEGENERATION IN ALZHEIMER'S DISEASER01AG073260 · NIA · BAYLOR COLLEGE OF MEDICINE · PI BELLEN, HUGO J · 2021 to 2025
$2.6MUCLA clinical site for the investigation of undiagnosed disordersU01NS134356 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI MARTINEZ-AGOSTO, JULIAN, NELSON, STANLEY F. · 2023 to 2023
$936kDepartment of Health NIHR-RP-2016-07-019Intramural NIH HHS Z01 OD022005NHGRI NIH HHS R01 HG009141NHGRI NIH HHS UM1 HG008900NIA NIH HHS R01 AG073260NICHD NIH HHS P30 HD024064NICHD NIH HHS P50 HD103555NICHD NIH HHS P50 HD105351NIGMS NIH HHS R01 GM134539NIH HHS R24 OD022005NIH HHS R24 OD031447NINDS NIH HHS R01 NS035129NINDS NIH HHS U01 NS134356NINDS NIH HHS U54 NS093793
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.
Indexed as
Drosophila ProteinsNervous System DiseasesAdultAnimalsDrosophilaEndoribonucleasesHumansMutationRNA, MessengerDrosophila ProteinsEndoribonucleasesInts11 protein, DrosophilaRNA, Messengerbrain atrophyCPSF3Ldelayed language developmentdevelopmental delaydIntS11Drosophilaimpaired motor developmentintellectual disabilityINTS11
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Registered trials
NCT02450851ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.