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Publications

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Ppublish 3 citations

PubMed: 37437211 DOI: 10.1093/brain/awad231

Models of KPTN-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes.

Brain 146(11):4766-4783

Authors: Maria O Levitin, Lettie E Rawlins, Gabriela Sanchez-Andrade, Osama A Arshad, Stephan C Collins, Stephen J Sawiak, Phillip H Iffland, Malin H L Andersson, Caleb Bupp, Emma L Cambridge, Eve L Coomber, Ian Ellis, Johanna C Herkert, Holly Ironfield, Logan Jory, Perrine F Kretz, Sarina G Kant, Alexandra Neaverson, Esther Nibbeling, Christine Rowley, Emily Relton, Mark Sanderson, Ethan M Scott, Helen Stewart, Andrew Y Shuen, John Schreiber, Liz Tuck, James Tonks, Thorkild Terkelsen, Conny van Ravenswaaij-Arts, Pradeep Vasudevan, Olivia Wenger, Michael Wright, Andrew Day, Adam Hunter, Minal Patel, Christopher J Lelliott, Peter B Crino, Binnaz Yalcin, Andrew H Crosby, Emma L Baple, Darren W Logan, Matthew E Hurles, Sebastian S Gerety

Affiliations

  • Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  • Evox Therapeutics Limited, Oxford OX4 4HG, UK.
  • RILD Wellcome Wolfson Medical Research Centre, University of Exeter, Exeter EX2 5DW, UK.
  • Peninsula Clinical Genetics Service, Royal Devon University Healthcare NHS Foundation Trust, Exeter EX1 2ED, UK.
  • INSERM Unit 1231, Université de Bourgogne Franche-Comté, Dijon 21078, France.
  • Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, UK.
  • Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK.
  • Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Spectrum Health, Helen DeVos Children's Hospital, Grand Rapids, MI 49503, USA.
  • Department of Clinical Genetics, Alder Hey Children's Hospital, Liverpool L14 5AB, UK.
  • Department of Genetics, University Medical Centre, University of Groningen, Groningen 9713 GZ, The Netherlands.
  • Haven Clinical Psychology Practice Ltd, Bude, Cornwall EX23 9HP, UK.
  • IGBMC, UMR7104, INSERM, Illkirch 67404, France.
  • Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, The Netherlands.
  • Department of Clinical Genetics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
  • Open Targets, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  • Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
  • Laboratory for Diagnostic Genome Analysis, Department of Clinical Genetics, Leiden University Medical Center, Leiden 3015 GD, The Netherlands.
  • Institute of Metabolic Science, Cambridge University, Cambridge CB2 0QQ, UK.
  • Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7YH, UK.
  • New Leaf Center, Clinic for Special Children, Mount Eaton, OH 44659, USA.
  • Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford OX3 7HE, UK.
  • London Health Sciences Centre, London, ON N6A 5W9, Canada.
  • Division of Medical Genetics, Department of Pediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5W9, Canada.
  • Department of Neurology, Children's National Medical Center, Washington DC 20007, USA.
  • Department of Clinical Genetics, Aarhus University Hospital, Aarhus DK-8200, Denmark.
  • Department of Clinical Genetics, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester LE1 7RH, UK.
  • Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne NE1 7RU, UK.
  • Qkine Ltd. Cambridge CB5 8HW, UK.
  • Waltham Petcare Science Institute, Waltham on the Wolds LE14 4RT, UK.

Abstract

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.

MeSH

Brain, Stem Cells, Therapeutics, Microscopy, Electron, Scanning Transmission, Neurology, Phenotype, Mechanistic Target Of Rapamycin Complex 1

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