Evidence map›Paper›PMID 39824192›Full record

ArticleAmerican journal of human genetics2025

Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy.

Rebecca Buchert, Martin D Burkhalter, Chrisovalantou Huridou, Linda Sofan, Timo Roser, Kirsten Cremer, Javeria Raza Alvi, Stephanie Efthymiou, Tawfiq Froukh, Sughra Gulieva and 24 more

Abstract read
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In one paragraph

Article in American journal of human genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

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.

2 · The registry

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

34 authors.

Rebecca BuchertInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. Electronic address: rebecca.buchert@med.uni-tuebingen.de.
Martin D BurkhalterDepartment of Experimental and Clinical Pharmacology and Pharmacogenomics, Division of Pharmacogenomics, University of Tübingen, Tübingen, Germany.
Chrisovalantou HuridouInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Department of Human Genetics, Ruhr University Bochum, Bochum, Germany.
Linda SofanInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Timo RoserDivision of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
Kirsten CremerInstitute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn, Germany.
Javeria Raza AlviDepartment of Pediatric Neurology, Institute of Child Health, Children's Hospital Lahore, Lahore, Pakistan.
Stephanie EfthymiouDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
Tawfiq FroukhDepartment of Biotechnology and Genetic Engineering, Philadelphia University, Amman, Jordan.
Sughra GulievaMediClub Hospital, Baku, Azerbaijan.
Ulviyya GuliyevaMediClub Hospital, Baku, Azerbaijan.
Moath HamdallahPediatrics Department, An-Najah National University Hospital, Nablus, Palestine.
Muriel Holder-EspinasseClinical Genetics Department, Guy's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, UK.
Rauan KaiyrzhanovDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
Doreen KlinglerInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Mahmoud KokoDepartment of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Lars MatthiesInstitute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn, Germany.
Joohyun ParkInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Marc SturmInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Ana VelicProteome Center Tübingen, University of Tübingen, Tübingen, Germany.
Stephanie SprangerMVZ Humangenetik Bremen, Limbach Genetics, Bremen, Germany.
Tipu SultanDepartment of Pediatric Neurology, Institute of Child Health, Children's Hospital Lahore, Lahore, Pakistan.
Hartmut EngelsInstitute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn, Germany.
Holger LercheDepartment of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Henry HouldenDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
Alistair T PagnamentaNIHR Oxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK.
Ingo BorggraefeDivision of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
Yvonne WeberDepartment of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Penelope E BonnenMolecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Reza MaroofianDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
Olaf RiessInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Center for Rare Disease, University of Tübingen, Tübingen, Germany; Genomics for Health in Africa (GHA), Africa-Europe Cluster of Research Excellence (CoRE).
Jonasz J WeberInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Department of Human Genetics, Ruhr University Bochum, Bochum, Germany.
Melanie PhilippDepartment of Experimental and Clinical Pharmacology and Pharmacogenomics, Division of Pharmacogenomics, University of Tübingen, Tübingen, Germany.
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Center for Rare Disease, University of Tübingen, Tübingen, Germany; Genomics for Health in Africa (GHA), Africa-Europe Cluster of Research Excellence (CoRE). Electronic address: tobias.haack@med.uni-tuebingen.de.

Funding

Personalized Functional Genomics for Mitochondrial Encephalopathy Gene DiscoveryR01NS083726 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI BONNEN, PENELOPE E · 2014 to 2025
$6.1M
NINDS NIH HHS R01 NS083726
6 · The paper itself

Abstract

Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting with intellectual disability and epilepsy. These variants partly affected KICS2 stability, compromised KICSTOR complex formation, and demonstrated a deleterious impact on nutrient-dependent mTORC1 regulation of 4EBP1 and S6K. Phosphoproteome analyses extended these findings to show that KICS2 variants changed the mTORC1 proteome, affecting proteins that function in translation, splicing, and ciliogenesis. Depletion of Kics2 in zebrafish resulted in ciliary dysfunction consistent with a role of mTORC1 in cilia biology. These in vitro and in vivo functional studies confirmed the pathogenicity of identified KICS2 variants. Our genetic and experimental data provide evidence that variants in KICS2 are a factor involved in intellectual disability due to its dysfunction impacting mTORC1 regulation and cilia biology.

Indexed as

EpilepsyIntellectual DisabilityMechanistic Target of Rapamycin Complex 1MutationAllelesAnimalsChildCiliaFemaleHumansMaleZebrafishMechanistic Target of Rapamycin Complex 1C12orf66ciliogenesisintellectual disabilityKICS2KICSTOR complexMTOR regulation

Identifiers

PMID39824192
PMCPMC11866974

What OpenQuestion holds

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LicenceCC BY-NC-ND
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Registered trials

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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.